N-substituted arylsulfonylamino hydroxamic acids useful as inhibitors of C-proteinase and for treating or preventing disorders related to unregulated collagen production

ABSTRACT

The present invention relates to a novel class of organic molecules capable of inhibiting C-proteinase, and to their use to regulate, modulate and/or inhibit abnormal collagen formation as a therapeutic approach towards the treatment of fibrotic disorders.

1. FIELD OF THE INVENTION

[0001] The present invention relates to a novel class of organicmolecules capable of inhibiting the enzyme C-proteinase, pharmaceuticalcompositions comprising the C-proteinase inhibitory compounds andmethods of using the compounds and compositions to regulate, modulateand/or inhibit collagen production and/or maturation as a therapeuticapproach towards the treatment or prevention of myriad diseases relatedto, or associated with, unregulated collagen production.

2. BACKGROUND OF THE INVENTION

[0002] Collagen Structure. At present, nineteen different types ofcollagens have been identified. These collagens, which include fibrillarcollagen types I, II and III, are synthesized as procollagen precursormolecules which contain peptide extensions at both their amino- andcarboxy-termini. These peptide extensions, referred to as “pro-regions,”are designated as N- and C-propeptides, respectively.

[0003] The pro-regions are typically cleaved upon secretion of theprocollagen triple helical precursor molecule from the cell to yield amature triple helical collagen molecule. Upon cleavage, the “mature”collagen molecule is capable of association, for example, into highlystructured collagen fibers. See e.g., Fessler and Fessler, 1978, Annu.Rev. Biochem. 47:129-162; Bornstein and Traub, 1979, in: The Proteins(eds. Neurath, H. and Hill, R. H.), Academic Press, New York, pp.412-632; Kivirikko et al., 1984, in: Extracellular Matrix Biochemistry(eds. Piez, K. A. and Reddi, A. H.), Elsevier Science Publishing Co.,Inc., New York, pp. 83-118; Prockop and Kivirikko, 1984, N. Engl. J.Med. 311:376-383; Kuhn, 1987, in: Structure and Function of CollagenTypes (eds. Mayne, R. and Burgeson, R. E.), Academic Press, Inc.,Orlando, Fla., pp. 1-42.

[0004] Diseases Associated With The Abnormal Production of Collagen. Avariety of critical diseases have been linked to inappropriate orunregulated collagen production and/or maturation. These diseasesinclude pathological fibrosis or scarring (including endocardialsclerosis), idiopathic interstitial fibrosis, interstitial pulmonaryfibrosis, perimuscular fibrosis, Symmers' fibrosis, pericentralfibrosis, hepatitis, dermatofibroma, billary cirrhosis, alcoholiccirrhosis, acute pulmonary fibrosis, idiopathic pulmonary fibrosis,acute respiratory distress syndrome, kidney fibrosis/glomerulonephritis,kidney fibrosis/diabetic nephropathy, scleroderma/systemic,scleroderma/local, keloids, hypertrophic scars, severe jointadhesions/arthritis, myelofibrosis, corneal scarring, cystic fibrosis,muscular dystrophy (duchenne's), cardiac fibrosis, muscularfibrosis/retinal separation, esophageal stricture and payronles disease.Further fibrotic disorders may be induced or initiated by surgery,including scar revision/plastic surgeries, glaucoma, cataract fibrosis,corneal scarring, joint adhesions, graft vs. host disease, tendonsurgery, nerve entrapment, dupuytren's contracture, OB/GYNadhesions/fibrosis, pelvic adhesions, peridural fibrosis, restenosis.One strategy for the treatment of these diseases is to inhibit thepathological overproduction of collagen. Thus, identification andisolation of molecules which control, inhibit and/or modulate theproduction of collagen are of major medical interest.

[0005] Relationship Between Collagen Formation and C-Proteinase. Recentevidence suggests that C-proteinase is the essential key enzyme thatcatalyzes the cleavage of the C-propeptide of, for example, fibrillarcollagens, including type I, type II, and type III collagen. See e.g.Prockep et al., 1998, Matrix Biol. 16:399-408; Lee et al., 1997, J.Biol. Chem. 272:19059-19066; Suzuk et al., 1996, Development122:3587-3595.

[0006] C-proteinase was first observed in the culture media of human andmouse fibroblasts (Goldberg et al., 1975, Cell 4:45-50; Kessler andGoldberg, 1978, Anal. Biochem. 86:463-469), and chick tendon fibroblasts(Duskin et al., 1978, Arch. Biochem. Biophys. 185:326-332; Leung et al.,1979, J. Biol. Chem. 254:224-232). An acidic proteinase which removesthe C-terminal propeptides from type I procollagen has also beenidentified. Davidson et al., 1979, Eur. J. Biochem. 100:551.

[0007] A partially purified protein having C-proteinase activity wasobtained from chick calvaria in 1982. Njieha et al., 1982, Biochemistry23:757-764. In 1985, chicken C-proteinase was isolated, purified andcharacterized from conditioned media of chick embryo tendons. Hojima etal., 1985, J. Biol. Chem. 260:15996-16003. Murine C-proteinase has beensubsequently purified from media of cultured mouse fibroblasts. Kessleret al., 1986, Collagen Relat. Res. 6:249-266; Kessler and Adar, 1989,Eur. J. Biochem. 186:115-121. Finally, the cDNA encoding humanC-proteinase has been identified (see, e.g., Takahara et al., 1994, J.Biol. Chem. 269:26280-26285; Li et al., 1996, Proc. Natl. Acad. Sci. USA93:5127-5130; Kessler at al., 1996, Science 271:360-362.

[0008] C-Proteinase Inhibitors. Experiments conducted with purifiedforms of chick and mouse C-proteinases indicate that C-proteinase isinstrumental in the formation of functional collagen fibers. Fertala etal., 1994, J. Biol. Chem. 269:11584. As a consequence of its criticalrole in collagen production and maturation, scientists have sought toidentify compounds that inhibit C-proteinase. See e.g., Hojima et al.,supra. Compounds identified to date include metal chelators (e.g., EDTA,phenanthroline, EGTA, basic amino acids (e.g., lysine and arginine),peptides (e.g., chymostatin, pepstatin A, and concanavalin A), proteins(e.g., α₂-macroglobulin, ovostatin, and fetal bovine serum), metals ions(e.g., Zn²⁺, Cu²⁺, and Cd²⁺), reducing agents (e.g., dithiothreitol),detergents (e.g., sodium dodecyl sulfate (SDS)) and certain salts andbuffers (e.g., phosphate, ammonium sulfate, sodium chloride and trishydrochloride). In contrast, microbial inhibitors such as leupeptin,phosphoramidon, antipain, bestatin, elastinal, and amastatin areconsidered to have weak or no effect on the activity of C-proteinase.For references discussing the various C-proteinase inhibitors identifiedto date, see Leung et al., supra; Ryhänen et al., 1982, Arch. Biochem.Biophys. 215:230-236; WO97/05865; and the references cited therein.

Matrix Metalloproteinase Hydroxamic Acid Inhibitors

[0009] C-proteinase belongs to the matrix metalloproteinase (MMP)superfamily of zinc endopeptidases which are involved in tissueremodeling. Members of the MMP family include MMP-1 (human collagenase),MMP-2 (gelatinase), and MMP-9 (human gelatinase B). See e.g. WO98/34918;Krumme et al., 1998, FEBS Lett. 436:209-212. The MMPs are characterizedby an active site zinc ion that plays an essential role in the enzymaticactivity of MMPs. Rational drug discovery efforts, involving theinhibition of MMPs, have focused on inhibitor classes that contain afunctional group that can coordinate the zinc ion and thereby inactivatethe target MMP. See e.g. Krumme et al., supra. One such inhibitor classare hydroxamic acids. As revealed by the x-ray crystal structuredetermination of hydroxamic acid:MMP cocrystals, the hydroxamic acidcoordinates the active site zinc in a bidentate manner via the hydroxyland carbonyl oxygens of the hydroxamic group. See Grams et al., 1995,Biochem. 34:14012-14020; Bode et al., 1994, EMBO J., 13:1263-1269.Despite their potent affinity as zinc coordinators, hydroxamic acidsdemonstrate a considerable degree of specificity within the MMP family.Thus a potent inhibitor of MMP-1 (human collagenase) may have onlyminimal potency against another MMP such as C-proteinase. Thus thedevelopment of potent hydroxamic acid inhibitors against a particularMMP requires considerable research effort and experimentation.

[0010] Development Of Compounds To Inhibit C-Proteinase Activity. Inview of its essential role in the formation and maturation of collagen,C-proteinase provides an ideal therapeutic target towards the treatmentor prevention of disorders related to, or associated with, unregulatedcollagen production or maturation. However, none of the C-proteinaseinhibitors identified to date have proven to be clinically effectivetherapeutics for the treatment of collagen-related diseases.Accordingly, there remains a need in the art for compounds that arespecific and potent inhibitors of C-proteinase, especially C-proteinaseinhibitory compounds which provide clinically relevant benefits in thetreatment or prevention of diseases associated with unregulated collagenproduction and/or maturation.

3. SUMMARY OF THE INVENTION

[0011] In one aspect, the present invention provides a novel class oforganic molecules that are potent and/or selective inhibitors ofC-proteinase. As a consequence of this activity, the compounds of theinvention are capable of modulating, regulating or inhibiting collagenproduction or maturation by affecting C-proteinase activity.

[0012] The compounds of the invention are generally N-substitutedarylsulfonylamino hydroxamic acids. In one embodiment, the compounds ofthe invention are N-aryl substituted arylsulfonylamino hydroxamic acidshaving the structural formula (I):

[0013] or pharmaceutically acceptable salts thereof, wherein:

[0014] a is an integer from 1 to 4;

[0015] b is an integer from 0 to 4;

[0016] c is an integer from 0 to 4;

[0017] Ar¹ is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀) aryl independently substituted with one or more Y¹, 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more Y¹;

[0018] Ar² is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀) aryl independently substituted with one or more Y², 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more Y²;

[0019] each Y¹ is independently selected from the group consisting of anelectron-donating functional group, an electron-withdrawing functionalgroup, and a lipophilic functional group; and

[0020] each Y² is independently selected from the group consisting of afunctional group having an acidic hydrogen, a functional group capableof participating in a hydrogen bond, a polar functional group, anelectron-withdrawing functional group, an electron-donating functionalgroup, and a lipophilic functional group,

[0021] with the provisos that:

[0022] (i) when a and b are each one, c is zero and Ar² is4′-methoxyphenyl, then Ar¹ is other than phenyl, 4′-flourophenyl,4′-chlorophenyl, 4′-trifluoromethylphenyl or 4′-methoxyphenyl; (ii) whena and b are each one, c is zero and Ar² is phenyl, then Ar¹ is otherthan 4′-chlorophenyl;

[0023] (iii) when a is two, b and c are each zero and Ar¹ is phenyl,then Ar² is other than 4′-chlorophenyl or 4′-bromophenyl; and

[0024] (iv) when a and b are each one, c is zero then Ar¹ is other thancarbocyclic aryl-lower alkyl, carbocyclic aryl, heterocyclic aryl,biaryl, biaryl-lower alkyl, heterocyclic aryl-lower alkyl, (N-aryl-loweralkylpiperazino)-lower alkyl

[0025] wherein, in proviso (iv), aryl represents monocyclic or bicyclicaryl, carbocyclic aryl represents monocyclic or bicyclic carbocyclicaryl and heterocyclic aryl represents monocyclic or bicyclicheterocyclic aryl.

[0026] In another embodiment, the compounds of the invention are N-arylsubstituted arylsulfonylamino hydroxamic acids having the structuralformula (II):

[0027] or pharmaceutically acceptable salts thereof, wherein:

[0028] d is an integer from 1 to 4;

[0029] e is an integer from 0 to 4;

[0030] f is an integer from 0 to 4;

[0031] Ar³ is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀) aryl independently substituted with one or more Y³, 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more Y³;

[0032] Ar⁴ is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀) aryl independently substituted with one or more Y⁴, 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more Y⁴;

[0033] each Y³ is independently selected from the group consisting of—R′, —OR′, —SR′, —NR′R′, —NO, —NO₂, —CN, -halogen, methyl, —SO₂NH₂ andtrihalomethyl; each Y⁴ is independently selected from the groupconsisting of —R′, —OR′, —OR″, —SR′, —SR″, —NR′R′, —NO₂, —CN, -halogen,-trihalomethyl, trihalomethoxy, —C(O)R′, —C(O)OR′, —C(O)NR′R′,—C(O)NR′OR′, —C(NR′R′)═NOR′, —NR′—C(O)R′, —SO₂R′, —SO₂R″, —NR′—SO₂—R′,—NR′—C(O)—NR′R′, tetrazol-5-yl, —NR′—C(O)—OR′, —C(NR′R′)═NR′, —S(O)—R′,—S(O)—R″, and —NR′—C(S)—NR′R′;

[0034] each R′ is independently selected from the group consisting of—H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl, and (C₂-C₈) alkynyl; and

[0035] each R″ is independently selected from the group consisting of(C₅-C₂₀) aryl and (C₅-C₂₀) aryl independently substituted with one ormore —OR′, —SR′, —NR′R′, —NO₂, —CN, halogen or trihalomethyl groups,

[0036] with the provisos that:

[0037] (i) when d and e are each one, f is zero and Ar⁴ is4′-methoxyphenyl, then Ar³ is other than phenyl, 4′-fluorophenyl,4′-chlorophenyl, 4′-trifluoromethylphenyl or 4′-methoxyphenyl;

[0038] (ii) when d and e are each one, f is zero and Ar⁴ is phenyl, thenAr³ is other than 4′-chlorophenyl;

[0039] (iii) when d is two, d and e are each zero and Ar³ is phenyl,then Ar⁴ is other than 4′-chlorophenyl or 4′-bromophenyl; and

[0040] (iv) when d and e are each one, f is zero then Ar³ is other thancarbocyclic aryl-lower alkyl, carbocyclic aryl, heterocyclic aryl,biaryl, biaryl-lower alkyl, heterocyclic aryl-lower alkyl, (N-aryl-loweralkylpiperazino)-lower alkyl

[0041] wherein, in proviso (iv), aryl represents monocyclic or bicyclicaryl, carbocyclic aryl represents monocyclic or bicyclic carbocyclicaryl and heterocyclic aryl represents monocyclic or bicyclicheterocyclic aryl.

[0042] In another embodiment, the compounds of the invention areN-cycloalkyl or N-heterocycloalkyl substituted arylsulfonylaminohydroxamic acids having the structural formula (III):

[0043] or pharmaceutically acceptable salts thereof, wherein:

[0044] g is an integer from 1 to 4;

[0045] h is an integer from 0 to 4;

[0046] i is an integer from 0 to 4;

[0047] Z is selected from the group consisting of (C₃-C₁₀) cycloalkyl,(C₃-C₁₀) cycloalkyl independently substituted with one or more Y⁵, 3-10membered heterocycloalkyl and 3-10 membered heterocycloalkylindependently substituted with one or more Y⁵;

[0048] Ar⁶ is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀) aryl independently substituted with one or more Y⁵, 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more Y⁶;

[0049] each Y⁵ is independently selected from the group consisting of alipophilic functional group, (C₅-C₂₀) aryl, (C₆-C₂₀) alkaryl, 5-20membered heteroaryl and 6-26 membered alk-heteroaryl;

[0050] each Y⁶ is independently selected from the group consisting of—R′, —OR′, —OR″, —SR′, —SR″, —NR′R′, —NO₂, —CN, -halogen,-trihalomethyl, trihalomethoxy, —C(O)R′, —C(O)OR′, —C(O)NR′R′,—C(O)NR′OR′, —C(NR′R′)═NOR′, —NR′—C(O)R′, —SO₂R′, —SO₂R″, —NR′—SO₂—R′,—NR′—C(O)—NR′R′, tetrazol-5-yl, —NR′—C(O)—OR′, —C(NR′R′)═NR′, —S(O)—R′,—S(O)—R″, and —NR′—C(S)—NR′R′; and

[0051] R′ and R″ are as previously defined for structure (II), with theproviso that when g and h is 1, i is 0, and Ar⁶ is phenyl, then Z isother than C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-lower alkyl, N-loweralkyl-piperazino-lower alkyl, (morpholino, thiomorpholino, piperidino,pyrrolidino, piperidyl or N-lower alkylpiperidyl)-lower alkyl.

[0052] In another embodiment, the compounds of the invention are N′substituted urea-arylsulfonylamino hydroxamic acids having thestructural formula (IV):

[0053] or pharmaceutically acceptable salts thereof, wherein:

[0054] j is an integer from 1 to 4;

[0055] k is an integer from 0 to 4;

[0056] Ar⁷ is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀)aryl independently substituted with one or more Y⁷, 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more Y⁷;

[0057] R¹⁸ and R¹⁹ are each independently selected from the groupconsisting of hydrogen, (C₁-C₈) alkyl, (C₂-C₈) alkenyl, (C₂-C₈) alkynyl,(C₃-C₁₀) cycloalkyl, (C₅-C₂₀) aryl, (C₅-C₂₀) substituted aryl, (C₆-C₂₆)alkaryl, (C₆-C₂₆) substituted alkaryl, 5-20 membered heteroaryl, 5-20membered substituted heteroaryl, 6-26 membered alk-heteroaryl, and 6-26membered substituted alk-heteroaryl; and

[0058] each Y⁷ is independently selected from the group consisting of anelectron-donating functional group, an electron-withdrawing functionalgroup, and a lipophilic functional group.

[0059] In another embodiment, the compounds of the present invention aresubstituted urea compounds having the structural formula (V):

[0060] or pharmaceutically acceptable salts thereof, wherein:

[0061] 1 is an integer from 1 to 4;

[0062] m is an integer from 0 to 4;

[0063] Ar⁸ is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀)aryl independently substituted with one or more Y⁸, 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more Y⁸;

[0064] R²⁰ is selected from the group consisting of hydrogen, (C₁-C₈)alkyl, (C₂-C₈) alkenyl, (C₂-C₈) alkynyl, (C₃-C₁₀) cycloalkyl, (C₅-C₂₀)aryl, (C₅-C₂₀) substituted aryl, (C₆-C₂₆) alkaryl, (C₆-C₂₆) substitutedalkaryl, 5-20 membered heteroaryl, 5-20 membered substituted heteroaryl,6-26 membered alk-heteroaryl, and 6-26 membered substitutedalk-heteroaryl;

[0065] R²¹ is independently selected from the group consisting ofhydrogen, (C₁-C₈) alkyl, (C₂-C₈) alkenyl, and (C₂-C₈) alkynyl; and

[0066] each Y⁸ is independently selected from the group consisting of anelectron-donating functional group, an electron-withdrawing functionalgroup, and a lipophilic functional group.

[0067] In another embodiment, the compounds of the present invention arebenzoyl substituted hydroxamic acids having the structural formula (VI):

[0068] or pharmaceutically acceptable salts thereof, wherein:

[0069] n is an integer from 1 to 4;

[0070] o is an integer from 0 to 4;

[0071] Ar⁹ is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀) aryl independently substituted with one or more Y⁹, 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more Y⁹; and

[0072] each R²⁵, R²⁶, R²⁷, R²⁸, R²⁹ and Y⁹ is independently selectedfrom the group consisting of an electron-donating functional group, anelectron-withdrawing functional group, and a lipophilic functionalgroup.

[0073] In a final embodiment, the compounds of the invention arebenzylsulfonyl substituted hydroxamic acids having the structuralformula (VII):

[0074] or pharmaceutically acceptable salts thereof, wherein:

[0075] p is an integer from 1 to 4;

[0076] q is an integer from 0 to 4;

[0077] Ar¹⁰ is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀)aryl independently substituted with one or more Y⁸, 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more Y⁹; and

[0078] each R³³, R³⁴, R³⁵, R³⁶, R³⁷ and Y¹⁰ is independently selectedfrom the group consisting of an electron-donating functional group, anelectron-withdrawing functional group, and a lipophilic functionalgroup.

[0079] In another aspect, the present invention provides pharmaceuticalcompositions comprising a therapeutically effective amount of one ormore of the above-described compounds and a pharmaceutically acceptablecarrier, diluent or excipient. Such a composition can be used in themethods of the invention to inhibit, regulate or modulate the productionor maturation of collagen by inhibiting C-proteinase activity and totreat or prevent a variety of collagen-related disorders.

[0080] In yet another aspect, the invention provides methods ofinhibiting C-proteinase activity. The method involves contacting theenzyme C-proteinase, or an active fragment or derivative thereof, withan amount of a compound or composition according to the inventioneffective to block collagen production. Methods of inhibitingC-proteinase in vivo can be used to inhibit, regulate or modulatecollagen production or maturation as a therapeutic approach towards thetreatment or prevention of disorders related to, or associated with,unregulated collagen production or maturation.

[0081] In a final aspect, the present invention provides methods for thetreatment or prevention of disorders related to, or associated with,inappropriate or unregulated collagen production or maturation. Themethod involves administering to an animal subject, including a human,an amount of a compound according to the invention, or a pharmaceuticalcomposition thereof, effective to treat or prevent the particularcollagen-related disorder.

[0082] Disorders which can be treated or prevented according to themethods of the invention include, but are not limited to, rheumatoidarthritis, scleroderma, pathological fibrosis or scarring.

4. DEFINITIONS

[0083] As used herein, the following terms shall have the followingmeanings:

[0084] “C-proteinase:” refers to an enzyme capable of processingcollagen molecules, derivatives or fragments of collagen molecules orprecursors of collagen molecules, collagen derivatives or collagenfragments by cleaving the amino acid sequence -Ala↓Asp-Asp-,-Gly↓Asp-Glu- and/or -Ala↓Asp-Gln- at the position marked with “↓”. Theterm “C-proteinase” includes human C-proteinase as well as derivatives,analogs, fragments and variants thereof capable of processing collagenmolecules as described above.

[0085] “Alkyl:” refers to a saturated branched, straight chain or cyclichydrocarbon radical. Typical alkyl groups include, but are not limitedto, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl,t-butyl, cyclobutyl, pentyl, isopentyl, cyclopentyl, hexyl, cyclohexyland the like. In preferred embodiments, the alkyl groups are (C₁-C₈)alkyl, more preferably (C₁-C₆) alkyl and most preferably (C₁-C₃) alkyl.

[0086] “Alkenyl:” refers to an unsaturated branched, straight chain orcyclic hydrocarbon radical having at least one carbon-carbon doublebond. The radical may be in either the cis or trans conformation aboutthe double bond(s). Typical alkenyl groups include, but are not limitedto, ethenyl, vinylidene, propenyl, propylidene, isopropenyl,isopropylidene, butenyl, butenylidene, isobutenyl, tert-butenyl,cyclobutenyl, pentenyl, isopentenyl, cyclopentenyl, hexenyl,cyclohexenyl and the like. In preferred embodiments, the alkenyl groupis (C₂-C₈) alkenyl, more preferably (C₂-C₆) alkenyl and most preferably(C₂-C₃) alkenyl.

[0087] “Alkynyl:” refers to an unsaturated branched, straight chain orcyclic hydrocarbon radical having at least one carbon-carbon triplebond. Typical alkynyl groups include, but are not limited to, ethynyl,propynyl, butynyl, isobutynyl, pentynyl, hexynyl and the like. Inpreferred embodiments, the alkynyl group is (C₂-C₈) alkynyl, morepreferably (C₂-C₆) and most preferably (C₂-C₃) alkynyl.

[0088] “Cycloalkyl:” refers to a cyclic or polycyclic saturated orunsaturated hydrocarbon radical. Typical cycloalkyl groups include, butare not limited to, cyclopropanyl, cyclobutanyl, cyclopentanyl,cyclohexanyl and higher cycloalkyls, adamantyl, cubanyl, prismanyl andhigher polycylicalkyls, etc. In preferred embodiments, the cycloalkyl is(C₃-C₁₀) cycloalkyl. Particularly preferred cycloalkyls are cyclohexanyland adamantyl.

[0089] “Heterocycloalkyl:” refers to a cycloalkyl moiety wherein one ofthe ring carbon atoms is replaced with another atom such as N, P, O, S,As, Ge, Se, Si, Te, etc. Typical heterocycloalkyls include, but are notlimited to, imidazolidyl, piperazyl, piperidyl, pyrazolidyl, pyrrolidyl,quinuclidyl, etc. In preferred embodiments, the cycloheteroalkyl is 5-10membered. Particularly preferred cycloheteroalkyls are morpholino,tetrahydrofuryl, and pyrrolidyl.

[0090] “Substituted Cycloalkyl or Cylcoheteroalkyl:” refers to acycloalkyl or cycloheteroalkyl radical wherein one or more hydrogenatoms are each independently replaced with another substituent. Typicalsubstituents include, but are not limited to, —R, —OR, —SR, —NRR, —CN,—NO₂, —C(O)R, —C(O)OR, —C(O)NRR, —C(NRR)═NR, —C(O)NROR, —C(NRR)═NOR,—NR—C(O)R, -tetrazol-5-yl, —NR—SO₂—R, —NR—C(O)—NRR, —NR—C(O)—OR,-halogen and -trihalomethyl where each R is independently —H, (C₁-C₈)alkyl, (C₂-C₈) alkenyl, (C₂-C₈) alkynyl, (C₅-C₂₀) aryl, (C₆-C₂₆)alkaryl, 5-20 membered heteroaryl, and 6-26 membered alk-heteroaryl asdefined herein.

[0091] “Aryl:” refers to an unsaturated cyclic hydrocarbon radicalhaving a conjugated n electron system. Typical aryl groups include, butare not limited to, penta-2,4-dienyl, phenyl, naphthyl, aceanthrylyl,acenaphthyl, anthracyl, azulenyl, chrysenyl, indacenyl, indanyl,ovalenyl, perylenyl, phenanthrenyl, phenalenyl, picenyl, pyrenyl,pyranthrenyl, rubicenyl and the like. In preferred embodiments, the arylgroup is (C₅-C₂₀) aryl, more preferably (C₅-C₁₀) aryl and mostpreferably phenyl.

[0092] “Substituted Aryl:” refers to an aryl radical wherein one or morehydrogen atoms are each independently replaced with another substituent.Typical substituents include, but are not limited to, —R, —OR, —SR,—NRR, —CN, —NO₂, —C(O)R, —C(O)OR, —C(O)NRR, —C(NRR)═NR, —C(O)NROR,—C(NRR)═NOR, —NR—C(O)R, —NR—C(O)—NRR, —NR—C(O)—OR, —NR—SO₂—R,-tetrazol-5-yl, -halogen and -trihalomethyl where each R isindependently —H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl, (C₂-C₈) alkynyl,(C₅-C₂₀) aryl, (C₆-C₂₆) alkaryl, heteroaryl and alk-heteroaryl asdefined herein.

[0093] “Alkaryl:” refers to a straight-chain (C₁-C₈) alkyl, (C₂-C₈)alkenyl or (C₂-C₈) alkynyl group wherein one of the hydrogen atomsbonded to the terminal carbon is replaced with an (C₅-C₂₀) aryl moiety.Alkaryl also refers to a branched-chain alkyl, alkenyl or alkynyl groupwherein one of the hydrogen atoms bonded to a terminal carbon isreplaced with an aryl moiety. Typical alkaryl groups include, but arenot limited to, benzyl, benzylidene, benzylidyne, benzenobenzyl,naphthalenobenzyl and the like. In preferred embodiments, the alkarylgroup is (C₆-C₂₆) alkaryl, i.e., the alkyl, alkenyl or alkynyl moiety ofthe alkaryl group is (C₁-C₆) and the aryl moiety is (C₅-C₂₀). Inparticularly preferred embodiments the alkaryl group is (C₆-C₁₃), i.e.,the alkyl, alkenyl or alkynyl moiety of the alkaryl group is (C₁-C₃) andthe aryl moiety is (C₅-C₁₀).

[0094] “Substituted Alkaryl:” refers to an alkaryl radical wherein oneor more hydrogen atoms on the aryl moiety are each independentlyreplaced with another substituent. Typical substituents include, but arenot limited to, —OR, —SR, —NRR, —CN, —NO₂, —C(O)R, —C(O)OR, —C(O)NRR,—C(S)NRR, —C(NRR)NR, —NR—C(O)R, —C(NRR)═NOR, —C(O)NROR, —NR—C(O)—NRR,-halogen and -trihalomethyl, where each R is independently —H, alkyl,alkenyl, alkynyl, aryl, alkaryl, heteroaryl or alk-heteroaryl as definedherein.

[0095] “Heteroaryl:” refers to an aryl moiety wherein one or more carbonatoms has been replaced with another atom, such as N, P, O, S, As, Ge,Se, Si, Te, etc. Typical heteroaryl groups include, but are not limitedto acridarsine, acridine, arsanthridine, arsindole, arsindoline,benzodioxole, benzothiadiazole, carbazole, β-carboline, chromane,chromene, cinnoline, furan, imidazole, indazole, indole, isoindole,indolizine, isoarsindole, isoarsinoline, isobenzofuran, isochromane,isochromene, isoindole, isophosphoindole, isophosphinoline,isoquinoline, isothiazole, isoxazole, naphthyridine, perimidine,phenanthridine, phenanthroline, phenazine, phosphoindole, phosphinoline,phthalazine, piazthiole, pteridine, purine, pyran, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline,quinoline, quinolizine, quinoxaline, selenophene, tellurophene,thiazopyrrolizine, thiophene and xanthene. In preferred embodiments, theheteroaryl group is a 5-20 membered heteroaryl, with 5-10 memberedheteroaryl being particularly preferred.

[0096] “Substituted Heteroaryl:” refers to a heteroaryl radical whereinone or more hydrogen atoms are each independently replaced with anothersubstituent. Typical substituents include, but are not limited to, —R,—OR, —SR, —NRR, —CN, —NO₂, —C(O)R, —C(O)OR, —C(O)NRR, —C(NRR)═NR,—C(O)NROR, —C(NRR)═NOR, —NR—C(O)R, —NR—C(O)—NRR, —NR—C(O)—OR, —NR—SO₂—R,-tetrazol-5-yl, -halogen and -trihalomethyl where each R isindependently —H, alkyl, alkenyl, alkynyl, aryl, alkaryl, heteroaryl andalk-heteroaryl as defined herein.

[0097] “Alk-heteroaryl:” refers to a straight-chain alkyl, alkenyl oralkynyl group where one of the hydrogen atoms bonded to a terminalcarbon atom is replaced with a heteroaryl moiety In preferredembodiments, the alkheteroaryl group is a 6-26 membered alkheteroaryl,i.e., the alkyl, alkenyl or alkynyl moiety of the alk-heteroaryl is(C₁-C₆) and the heteroaryl moiety is a 5-20-membered heteroaryl. Inparticularly preferred embodiments, the alk-heteroaryl is a 6-13membered alk-heteroaryl, i.e., the alkyl, alkenyl or alkynyl moiety is(C₁-C₃) and the heteroaryl moiety is a 5-10 membered heteroaryl.

[0098] “Substituted Alk-heteroaryl:” refers to an alk-heteroaryl radicalwherein one or more hydrogens on the heteroaryl moiety are eachindependently replaced with another substituent. Typical substituentsinclude, but are not limited to, —OR, —SR, —NRR, —CN, —NO₂, —C(O)R,—C(O)OR, —C(O)NRR, —C(S)NRR, —C(NRR)═NR, —NR—C(O)—NRR, —NR—C(O)—OR,—NR—SO₂—R, -tetrazol-5-yl, -halogen and -trihalomethyl, where each R isindependently —H, alkyl, alkenyl, alkynyl, aryl, alkaryl, heteroaryl oralk-heteroaryl as defined herein.

[0099] “Electron-donating functional group” An electron-donatingfunctional group is any functional group that produces an inductivefield effect by presenting a partial negative charge to the parent groupthat the functional group is attached to. As used herein, representativeelectron-donating groups include, but are not limited to, —Cl, —R, —OR,—SR, and —NRR, where each R is independently —H, (C₁-C₈) alkyl, (C₂-C₈)alkenyl or (C₂-C₈) alkynyl.

[0100] “Electron-withdrawing functional group” An electron-withdrawingfunctional group is any functional group that produces an inductivefield effect by presenting a partial positive charge to the parent groupthat the functional group is attached to. As used herein, representativeelectron-withdrawing functional groups include, but are not limited to,—F, —NO, —NO₂, —CN, -trihalomethyl, —SO₂NHR, —SO₂R, and —S(O)R, whereeach R is independently —H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl or (C₂-C₈)alkynyl.

[0101] “Lower Alkyl” defines branched or unbranched organic compoundswith up to and including 7, preferably up to and including 4 andadvantageously one or two carbon atoms.

[0102] “A lower alkyl group” is branched or unbranched and contains 1 to7 carbon atoms, preferably 1-4 carbon atoms, and represents for examplemethyl, ethyl, propyl, butyl, isopropyl, isobutyl and the like.

[0103] “Carbocylic aryl” represents monocyclic or bicyclic aryl, forexample phenyl or phenyl mono-, di- or tri-substituted by one, two orthree radicals selected from lower alkyl, lower alkoxy, hydroxy,halogen, cyano and trifluoromethyl or phenyl disubstituted on adjacentcarbon atoms by lower alkylenedioxy, such as methylenedioxy; or 1- or2-naphthyl. Preferred is phenyl or phenyl monosubstituted by loweralkoxy, halogen or trifluoromethyl.

[0104] “Heterocyclic aryl” represents monocyclic or bicyclic heteroaryl,for example pyridyl, quinolyl, isoquinolyl, benzothienyl, benzofuranyl,benzopyranyl, benzothiopyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl,isoxazolyl, triazolyl, tetrazolyl, pyrrazolyl, imidazolyl, thienyl, orany said radical substituted by lower alkyl or halogen. Pyridylrepresents 2-, 3- or 4-pyridyl, advantageously 2- or 3-pyridyl. Thienylrepresents 2- or 3-thienyl, advantageously 2-thienyl. Quinolylrepresents preferably 2-, 3- or 4-quinolyl, advantageously 2-quinolyl.Isoquionolyl represents preferably 1-, 3- or 4-isoquinolyl.Benzopyranyl, benzothiopyranyl represents preferably 3-benzopyranyl or3-benzothiopyranyl, respectively. Thiazolyl represents preferably 2- or4-thiazolyl, advantageously 4-thiazolyl. Triazolyl is preferably 1-, 2-or 5-(1,2,4-triazolyl). Tetrazolyl is preferably 5-tetrazolyl.Imidazolyl is preferably 4-imidazolyl.

[0105] “Biaryl” is preferably carbocyclic biaryl, e.g. biphenyl, namely2, 3 or 4-biphenyl, advantageously 4-biphenyl, each optionallysubstituted by e.g. lower alkyl, lower alkoxy, halogen, trifluoromethylor cyano.

[0106] “C₃-C₇-cycloalkyl” represents a saturated cyclic hydrocarbonoptionally substituted by lower alkyl which contains 3 to 7 ring carbonsand is advantageously cyclopentyl or cyclohexyl optionally substitutedby lower alkyl.

[0107] “Carbocyclic aryl-lower alkyl” represents preferably straightchain or branched aryl-C₁-C₄ alkyl in which carbocyclic aryl has meaningas defined above, e.g. benzyl or phenyl-(ethyl, propyl or butyl), eachunsubstituted or substituted on the phenyl ring as defined undercarbocyclic aryl above, advantageously optionally substituted benzyl.

[0108] “Heterocyclic aryl-lower alkyl” represents preferably straightchain or branched heterocyclic aryl-C₁-C₄-alkyl in which heterocyclicaryl has meaning as defined above, e.g. 2-, 3-, or 4-pyridylmethyl or(2-, 3-, or 4-pyridyl)-(ethyl, propyl or butyl); or 2- or3-thienylmethyl or (2- or 3-thienyl)-(ethyl, propyl or butyl); 2-, 3-,or 4-quinolylmethyl or (2-, 3- or 4-quinolyl)-(ethyl, propyl or butyl);or 2- or 4-thiazolylmethyl or (2- or 4-thiazolyl)-(ethyl, propyl orbutyl); and the like.

“Cycloalkyl-lower alkyl” represents preferably (cyclopentyl- orcyclohexyl)-(methyl or ethyl), and the like.

[0109] “Biaryl-lower alkyl” represents preferably 4-biphenylyl-(methylor ethyl) and the like.

5. DETAILED DESCRIPTION OF THE INVENTION

[0110] The present invention provides a novel class of organic compoundscapable of inhibiting the enzyme C-proteinase, pharmaceuticalcompositions comprising one or more of such compounds, and methods ofusing the compounds to inhibit, regulate or modulate collagen formationor maturation as a therapeutic approach towards the treatment orprevention of diseases related to, or associated with, unregulatedcollagen production or maturation.

[0111] 5.1 The Compounds

[0112] In one embodiment, compounds which are capable of inhibitingC-proteinase according to the invention, and which can therefore be usedin methods to inhibit, modulate or regulate collagen production ormaturation or to treat or prevent diseases related to, or associatedwith, unregulated collagen production or maturation are generally N-arylsubstituted arylsulfonylamino hydroxamic acids having the structuralformula (I):

[0113] or pharmaceutically acceptable salts thereof, wherein:

[0114] a is an integer from 1 to 4;

[0115] b is an integer from 0 to 4;

[0116] c is an integer from 0 to 4;

[0117] Ar¹ is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀) aryl independently substituted with one or more Y¹, 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more Y¹;

[0118] Ar² is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀) aryl independently substituted with one or more Y², 5-20membered heteroaryl, and 5-20 membered heteroaryl independentlysubstituted with one or more Y²;

[0119] each Y¹ is independently selected from the group consisting of anelectron-donating functional group, an electron-withdrawing functionalgroup, and a lipophilic functional group; and

[0120] each Y² is independently selected from the group consisting of afunctional group having an acidic hydrogen, a functional group capableof participating in a hydrogen bond, a polar functional group, anelectron-withdrawing functional group, an electron-donating functionalgroup, and a lipophilic functional group;

[0121] with the provisos that:

[0122] (i) when a and b are each one, c is zero and Ar² is4′-methoxyphenyl, then Ar¹ is other than phenyl, 4′-flourophenyl,4′-chlorophenyl, 4′-trifluoromethylphenyl or 4′-methoxyphenyl; (ii) whena and b are each one, c is zero and Ar² is phenyl, then Ar¹ is otherthan 4′-chlorophenyl;

[0123] (iii) when a is two, b and c are each zero and Ar¹ is phenyl,then Ar² is other than 4′-chlorophenyl or 4′-bromophenyl; and

[0124] (iv) when a and b are each one, c is zero then Ar¹ is other thancarbocyclic aryl-lower alkyl, carbocyclic aryl, heterocyclic aryl,biaryl, biaryl-lower alkyl, heterocyclic aryl-lower alkyl, or(N-aryl-lower alkylpiperazino)-lower alkyl,

[0125] wherein, in proviso (iv), aryl represents monocyclic or bicyclicaryl, carbocyclic aryl represents monocyclic or bicyclic carbocyclicaryl and heterocyclic aryl represents monocyclic or bicyclicheterocyclic aryl.

[0126] Typical electron-donating functional groups that areindependently selected for Y¹ and Y² in compounds of formula (I)include, but are not limited to, —Cl, —R, —OR, —SR, —NRR, where each Ris independently —H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl or (C₂-C₈) alkynyl.Particularly preferred electron-donating groups are —Cl, and —OCH₃.

[0127] Functional groups having an acidic hydrogen that are suitable forY² in compounds of formula (I) include, but are not limited to, —COOH,—SO₃H, —P(O) (OH)₂, —C(O)—NH—OH,

[0128] where each R is independently H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl,(C₂-C₈) alkynyl, (C₅-C₂₀) aryl, (C₆-C₂₆) alkaryl, 5-20 memberedheteroaryl, and 6-26 membered alk-heteroaryl as defined herein.Functional groups capable of participating in a hydrogen bond that aresuitable for Y² in compounds of formula (I) include bothhydrogen-donating groups and hydrogen accepting groups. Typical hydrogendonating groups independently selected for Y² include, but are notlimited to, —C(NHR)═N—OH, —NH—C(O)R, —NH—C(O)—NRR, —C(S)NHR, —C(O)NHR,—CO₂H, —NH₂, —C(NHR)═NR, —NH—C(O)—OR, —NH—SO₂—R, —NH—C(S)—NRR where eachR is independently —H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl, (C₂-C₈) alkynyl,(C₅-C₂₀) aryl, (C₆-C₂₆) alkaryl, 5-20 membered heteroaryl, and 6-26membered alk-heteroaryl as defined herein. Typical hydrogen acceptinggroups selected for Y² include, but are not limited to, —CO₂R, SO₂R,—OR, SR, C(O)—R, —C(O)NRR, —C(S)NRR, —NH—C(O)R, —NR—C(O)—NRR,—NR—C(S)—NRR, and —S(O)—R where each R is independently —H, (C₁-C₈)alkyl, (C₂-C₈) alkenyl, (C₂-C₈) alkynyl, (C₅-C₂₀) aryl, (C₆-C₂₆)alkaryl, 5-20 membered heteroaryl and 6-26 membered alk-heteroaryl asdefined herein. Typical polar functional groups selected for Y² incompounds of formula (I) include, but are not limited to —C≡N, —OR, and—SR where R is independently —H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl, (C₂-C₈)alkynyl, (C₅-C₂₀) aryl, (C₆-C₂₆) alkaryl, 5-20 membered heteroaryl and6-26 membered alk-heteroaryl as defined herein.

[0129] Typical electron-withdrawing functional groups that areindependently selected for Y¹ and Y² in compounds of formula (I)include, but are not limited to —F, —NO, —NO₂, —CN, -trihalomethyl, and—SO₂NHR; where each R is independently H, (C₁-C₈) alkyl, (C₂-C₈)alkenyl, (C₂-C₈) alkynyl, (C₅-C₂₀) aryl, (C₆-C₂₆) alkaryl, 5-20 memberedheteroaryl and 6-26 membered alk-heteroaryl as defined herein.Furthermore, groups such as —SO₂R and —S(O)R may be selected for Y².

[0130] Typical lipophilic functional groups that are selected for Y¹ andY² include, but are not limited to n-butyl, alkoxy such as butoxy, andhalogen.

[0131] One group of preferred compounds according to structure (I) arethose compounds wherein Ar¹ is selected from the group consisting of(C₅-C₂₀) aryl and (C₅-C₂₀) aryl independently substituted with one ormore Y¹ and Ar² is selected from the group consisting of (C₅-C₂₀) aryland (C₅-C₂₀) aryl independently substituted with one or more Y².Particularly preferred compounds according this aspect of the inventionare those compounds having the structural formula (Ia):

[0132] or pharmaceutically acceptable salts thereof, wherein:

[0133] a is an integer from 1 to 4;

[0134] b is an integer from 0 to 4;

[0135] c is an integer from 0 to 4;

[0136] R¹, R², R³, R⁴ and R⁵ are each independently selected from thegroup consisting of —H, an electron-donating functional group, anelectron-withdrawing functional group, and a lipophilic functionalgroup;

[0137] R⁶, R⁷, R⁸, R⁹ and R¹⁰ are each independently selected from thegroup consisting of —H, a functional group having an acidic hydrogen, afunctional group capable of participating in a hydrogen bond (e.g., ahydrogen-donating or a hydrogen-accepting functional group), a polarfunctional group, an electron-withdrawing functional group, anelectron-donating functional group, and a lipophilic functional group;

[0138] with the provisos that

[0139] (i) when a and b are each one, c is other than zero; and

[0140] (ii) when a is two, b and c are each zero and R¹, R², R⁴, R⁵, R⁶,R⁷, R⁹ and R¹⁰ are each —H, then R⁸ is other than —F or —Cl.

[0141] Electron-donating functional groups useful for substituting theA-phenyl ring of compounds according to structure (Ia) include —R, —Cl,—OR, —SR, and —NRR, where each R is independently —H, (C₁-C₈) alkyl,(C₂-C₈) alkenyl or (C₂-C₈) alkynyl. Particularly preferredelectron-donating groups are —Cl and —OCH₃.

[0142] Functional groups having an acidic hydrogen useful forsubstituting the B-phenyl ring of compounds according to structure (Ia)include —COOH, —SO₃H, —P(O) (OH)₂, —C(O)—NH—OH,

[0143] where each R is independently —H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl,(C₂-C₈) alkynyl, (C₅-C₂₀) aryl, (C₆-C₂₆) alkaryl, 5-20 memberedheteroaryl and 6-26 membered alk-heteroaryl as defined herein; and COOHis particularly preferred. Hydrogen-donating/accepting functional groupsuseful for substituting the B-phenyl ring of compounds according tostructure (Ia) include —C(NHR)═N—OH, —NH—C(O)R, —NH—C(O)—NRR, —C(S)NHR,—C(O)NHR, —CO₂H, —NH₂, —C(NHR)═NR, —NH—(CO)—OR and —NH—SO₂—R, with—NH—C(O)—NRR being particularly preferred. Polar functional groupsuseful for substituting the B-phenyl ring of compounds according tostructure (Ia) include —C≡N, —OR, and, —SR, with —OR being particularlypreferred. Electron-withdrawing functional groups useful forsubstituting the B-phenyl ring of compounds according to structure (Ia)include —SOR, —S(O)R, —NO₂, and —CF₃, with —SO₂R being particularlypreferred.

[0144] One group of preferred compounds according to structure (Ia) arethose compounds wherein the A- and/or B-phenyl rings are eitherunsubstituted or mono-substituted. When mono-substituted, the A-phenylring may be substituted at either the ortho, meta or para position;however, para-substitution is preferred. When mono-substituted, theB-phenyl ring may also be substituted at the ortho, meta or paraposition, with para-substitution being preferred.

[0145] Another group of preferred compounds according to structure (Ia)are those compounds wherein the A-phenyl ring is di-substituted(preferably at the meta- and para-positions) and/or the B-phenyl ring iseither unsubstituted or mono-substituted (preferably at thepara-position).

[0146] Another group of preferred compounds according to structure (Ia)are those compounds having the structural formula (Ia′):

[0147] or pharmaceutically acceptable salts thereof, wherein:

[0148] a is an integer from 1 to 4;

[0149] b is an integer from 0 to 4;

[0150] R³, R⁴ and R⁵ are each independently selected from the groupconsisting of —H, an electron-donating functional group, anelectron-withdrawing functional group and a lipophilic functional group;and

[0151] R⁶, R⁷ and R⁸ are each independently selected from the groupconsisting of —H, a functional group having an acidic hydrogen, afunctional group capable of participating in a hydrogen bond (e.g., ahydrogen-donating or a hydrogen-accepting functional group), a polarfunctional group, an electron-withdrawing functional group, anelectron-donating functional group, and a lipophilic functional group;with the provisos that

[0152] (i) when a is 1, b is other than 1; and

[0153] (ii) when a is two and b is zero and R³, R⁴, R⁵, R⁶, R⁷ are each—H, then R⁸ is other than —F or —Cl.

[0154] One group of preferred compounds according to structure (Ia′) arethose compounds wherein:

[0155] a is an integer from 1 to 3;

[0156] b is an integer from 0 to 2;

[0157] R³ and R⁴ are each independently selected from the groupconsisting of —H, halogen (preferably —F or —Cl), —OR and trihalomethyl(preferably —CF₃);

[0158] R⁵ is selected from the group consisting of —H and —OR(preferably —H);

[0159] R⁶ is selected from the group consisting of —H, —C(O)OR,—C(NH₂)═NOH and —SO₂R;

[0160] R⁷ is selected from the group consisting of —H and —C(NH₂)═NOH;and/or

[0161] R⁸ is selected from the group consisting of —H, —OR, —NO₂,—C(O)OR, —SO₂R and —C(NH₂)═NOH; and

[0162] each R is independently selected from the group consisting of —Hand (C₁-C₃) alkyl (preferably methyl), (C₂-C₃) alkenyl and (C₁-C₃)alkynyl;

[0163] with the provisos that

[0164] (i) when a is 1, b is other than 1; and

[0165] (ii) when a is two and b is zero and R³, R⁴, R⁵, R⁶, R⁷ are each—H, then R⁸ is other than —F or —Cl.

[0166] Particularly preferred compounds according to structure (Ia′) areas follows: Compound (FG) a b R³ R⁴ R⁵ R⁶ R⁷ R⁸ 121 2 1 —H —H —H —H —H—OMe 122 3 1 —H —H —H —H —H —OMe 123 1 0 —H —H —H —H —H —OMe 124 2 0 —H—H —H —H —H —OMe 125 3 0 —H —H —H —H —H —OMe 126 2 2 —H —H —H —H —H —OMe128 1 2 —H —H —H —H —H —OMe 134 3 2 —H —H —H —H —H —OMe 202 1 0 —OMe —H—H —H —H —OMe 204 1 2 —OMe —H —H —H —H —OMe 206 2 2 —OMe —H —H —H —H—OMe 208 2 0 —OMe —H —H —H —H —OMe 1268 2 2 —H —H —H —H —H —NO₂ 1300 2 2—Cl —H —H —H —H —OMe 1301 2 2 —OMe —OMe —H —H —H —OMe 1405 2 2 —H —H—OMe —H —H —C(O)OH 1455 2 2 —OMe —H —H —H —H —C(NH₂)═NOH 1456 2 2 —OMe—H —H —H —C(NH₂)═NOH —H 1459 2 2 —OMe —H —H —C(NH₂)═NOH —H —H 1460 2 2—OMe —H —H —H —H —SO₂Me 1465 2 2 —OMe —H —H —SO₂Me —H —H 1468 2 2 —OMe—H —H —C(O)OMe —H —H 1474 2 1 —C₅H₁₁ —H —H —H —H —C(NH₂)═NOH

[0167] In another preferred embodiment of the compounds of structure(I), Ar¹ is (C₁-C₆) alkoxyphenyl (particularly 4′-(C₁-C₆) alkoxyphenyl).Particularly preferred compounds according to this aspect of theinvention are those compounds having the structural formula (Ib):

[0168] or pharmaceutically acceptable salts thereof, wherein:

[0169] a, b, c and Ar² are as previously defined for structure (I)

[0170] One group of preferred compounds according to structure (Ib) arethose compounds wherein:

[0171] a, b and c are as previously defined for structure (I);

[0172] Ar² is selected from the group consisting of (C₅-C₁₀) aryl,(C₅-C₁₀) aryl mono-substituted with Y², 5-10 membered heteroaryl and5-10 membered heteroaryl mono-substituted with Y²;

[0173] each Y² is independently selected from the group consisting of—R, —OR, —SR, —NRR, —NO₂, —CN, halogen, —NR—C(O)—NRR, tetrazole,trihalomethyl, —C(O)R, —C(O)OR, —C(O)NRR, —C(NRR)═NOR, —C(O)NROR and—SO₂R; and

[0174] each R is independently selected from the group consisting of —H,(C₁-C₈) alkyl, (C₂-C₈) alkenyl or (C₂-C₈) alkynyl,

[0175] with the provisos that when a and b is 1 then c is other than 0;

[0176] Another preferred group of compounds according to structure (Ib)are those compounds wherein:

[0177] a, b and c are as previously defined for structure (I);

[0178] Ar² is selected from the group consisting of phenyl, phenylmono-substituted with Y², thienyl and thienyl mono-substituted with Y²;

[0179] each Y² is independently selected from the group consisting of—OR, —NRR, —NO₂, —NR—C(O)—NRR, tetrazole, —CN, halogen, trihalomethyl,—C(O)R, —C(O)OR, —C(O)NRR, —C(NH₂)═NOH, —C(O)NHOH and —SO₂R; and

[0180] each R is independently selected from the group consisting of(C₁-C₈) alkyl, (C₂-C₈) alkenyl and (C₂-C₈) alkynyl.

[0181] Particularly preferred compounds according to structure (Ib) areas follows: Compound (EG) a b c Ar² 202 1 0 0

204 1 2 0

206 2 2 0

208 2 0 0

1455 2 2 0

1456 2 2 0

1459 2 2 0

1460 2 2 0

1465 2 2 0

1468 2 2 0

1471 2 2 0

1489 2 2 0

[0182] In still another preferred embodiment of the compounds ofstructure (I), Ar² is mono- or di-substituted phenyl. Particularlypreferred compounds according to this aspect of the invention are thosecompounds having the structural formula (Ic):

[0183] or pharmaceutically acceptable salts thereof, wherein:

[0184] Ar¹, a, b and c are as previously defined for structure (I);

[0185] R¹¹, R¹² and R¹³ are each independently selected from the groupconsisting of —R, —OR, —SR, —NRR, —NO₂, —CN, halogen, trihalomethyl,—C(O)R, —C(O)OR, —C(O)NRR, —C(NRR)═NOR, —NR—C(O)R, —NR—C(O)—NRR,—NR—C(O)—OR, tetrazol-5-yl, —NR—SO₂—R, and —SO₂R; and

[0186] each R is independently selected from the group consisting of —H,(C₁-C₈) alkyl, (C₂-C₈) alkenyl and (C₂-C₈) alkynyl.

[0187] One preferred embodiment of the compounds of structure (Ic) arethose compounds wherein at least two of R¹¹, R¹² and R¹³ are —H:

[0188] Another preferred embodiment of the compounds of structure (Ic)are those compounds according to structure (Ic′):

[0189]  and pharmaceutically acceptable salts thereof, wherein:

[0190] a, b, Ar¹, R¹¹, R¹² and R¹³ are as previously defined forstructure (Ic).

[0191] One particularly preferred group of compounds according tostructure (Ic′) are those compounds wherein:

[0192] a, b and c are as previously defined for structure (I);

[0193] Ar¹ is selected from the group consisting of phenyl, pyridinyl,1,3-benzodioxolyl, 1,4-benzodioxanyl, thienyl and the above-describedheteroaryl groups which are independently substituted (preferablymono-substituted) with one or more Y¹ groups;

[0194] R¹¹, R¹² and R¹³ are each independently selected from the groupconsisting of —H, —OR, —C(O)R, —C(O)OR, —C(O)NRR, —C(NH₂)NOH, —NH—C(O)R,—NR—C(O)—NRR, —NR—C(O)—OR, —NR—SO₂—R, tetrazol-5-yl and —SO₂R; and

[0195] each R is independently selected from the group consisting ofhydrogen, (C₁-C₃) alkyl (preferably methyl), (C₂-C₃) alkenyl and (C₂-C₃)alkynyl.

[0196] Another particularly preferred group of compounds according tostructure (Ic′) are as follows: Compound (FG) a b Ar¹ R¹¹ R¹² R¹³ 1132 22 pyrid-2-yl —OMe —H —H 1374 2 1 1,4-benzodioxan-2-yl —OMe —H —H 1273 21 1,3-benzodioxol-5-yl —OMe —H —H 1357 2 1 1,3-benzodioxol-5-yl—NH—C(O)Me —H —H 1372 2 1 1,3-benzodioxol-5-yl —O(nBu) —H —H 1410 2 11,3-benzodioxol-5-yl —OMe —OMe —H 1464 2 1 1,3-benzodioxol-5-yl —SO₂Me—H —H 1369 2 1 1,3-benzodioxol-5-yl —C(NH₂)═NOH —H —H 1458 2 11,3-benzodioxol-5-yl —H —C(NH₂)═NOH —H 1414 2 2 thien-2-yl —H —H —H 14162 2 thien-2-yl —O(nBu) —H —H 1411 2 2 thien-2-yl —NH—C(O)Me —H —H 1463 22 thien-2-yl —SO₂Me —H —H 1457 2 2 thien-2-yl —H —C(NH₂)═NOH —H 1409 2 2thien-2-yl —C(NH₂)═NOH —H —H 121 2 1 phenyl —OMe —H —H 122 3 1 phenyl—OMe —H —H 123 1 0 phenyl —OMe —H —H 124 2 0 phenyl —OMe —H —H 125 3 0phenyl —OMe —H —H 126 2 2 phenyl —OMe —H —H 128 1 2 phenyl —OMe —H —H134 3 2 phenyl —OMe —H —H 202 1 0 4′-methoxyphenyl —OMe —H —H 204 1 24′-methoxyphenyl —OMe —H —H 206 2 2 4′-methoxyphenyl —OMe —H —H 208 2 04′-methoxyphenyl —OMe —H —H 1300 2 2 4′-chlorophenyl —OMe —H —H 1405 2 22′-methoxyphenyl —COOH —H —H 1455 2 2 4′-methoxyphenyl —C(NH₂)═NOH —H —H1456 2 2 4′-methoxyphenyl —H —C(NH₂)═NOH —H 1460 2 2 4′-methoxyphenyl—SO₂Me —H —H 1268 2 2 phenyl —NO₂ —H —H 1459 2 2 4′-methoxyphenyl —H —H—C(NH₂)═NOH 1465 2 2 4′-methoxyphenyl —H —H —SO₂Me 1468 2 24′-methoxyphenyl —H —H —C(O)Me

[0197] In another embodiment, the compounds that are capable ofinhibiting c-proteinase according to the invention, and which cantherefore be used in methods to inhibit, modulate or regulate collagenproduction or maturation or to treat diseases related to, or associatedwith, unregulated collagen production or maturation are generally N-arylsubstituted arylsulfonylamino hydroxamic acids having the structuralformula (II):

[0198] or pharmaceutically acceptable salts thereof, wherein:

[0199] d is an integer from 1 to 4;

[0200] e is an integer from 0 to 4;

[0201] f is an integer from 0 to 4;

[0202] Ar³ is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀) aryl independently substituted with one or more Y³, 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more Y³;

[0203] Ar⁴ is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀) aryl independently substituted with one or more Y⁴, 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more Y⁴;

[0204] each Y³ is independently selected from the group consisting of—SO₂NH₂, —R′, —OR′, —SR′, —NR′R′, —NO₂, —CN, -halogen and trihalomethyl;

[0205] each Y⁴ is independently selected from the group consisting of—R′, —OR′, —OR″, —SR′, —SR″, —NR′R′, —NO₂, —CN, -halogen,-trihalomethyl, trihalomethoxy, —C(O)R′, —C(O)OR′, —C(O)NR′R′,—C(O)NR′OR′, —C(NR′R′)═NOR′, —NR′—C(O)R′, —SO₂R′, —SO₂R″, —NR′—SO₂—R′,—NR′—C(O)—NR′R′, tetrazol-5-yl, —NR′—C(O)—OR′, —C(NR′R′)═NR′, —S(O)—R′,—S(O)—R″, and —NR′—C(S)—NR′R′;

[0206] each R′ is independently selected from the group consisting of—H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl and (C₂-C₈) alkynyl; and

[0207] each R″ is independently selected from the group consisting of(C₅-C₂₀) aryl and (C₅-C₂₀) aryl independently substituted with one ormore —OR′, —SR′, —NR′R′, —NO₂, —CN, halogen or trihalomethyl groups,

[0208] with the provisos that:

[0209] (i) when d and e are each one, f is zero and Ar⁴ is4′-methoxyphenyl, then Ar³ is other than phenyl, 4′-fluorophenyl,4′-chlorophenyl, 4′-trifluoromethylphenyl or 4′-methoxyphenyl;

[0210] (ii) when d and e are each one, f is zero and Ar⁴ is phenyl, thenAr³ is other than 4′-chlorophenyl;

[0211] (iii) when d is two, d and e are each zero and Ar³ is phenyl,then Ar⁴ is other than 4′-chlorophenyl or 4′-bromophenyl; and

[0212] (iv) when d and e are each one, f is zero then Ar³ is other thancarbocyclic aryl-lower alkyl, carbocyclic aryl, heterocyclic aryl,biaryl, biaryl-lower alkyl, heterocyclic aryl-lower alkyl, or(N-aryl-lower alkylpiperazino)-lower alkyl

[0213] wherein, in proviso (iv), aryl represents monocyclic or bicyclicaryl, carbocyclic aryl represents monocyclic or bicyclic carbocyclicaryl and heterocyclic aryl represents monocyclic or bicyclicheterocyclic aryl.

[0214] In one group of preferred compounds according to structure (II),Ar³ is thienyl. Particularly preferred compounds according to thisaspect of the invention are those compounds having the structuralformula (IIa):

[0215] or pharmaceutically acceptable salts thereof, wherein d, e, f andAr⁴ are as previously defined for structure (II).

[0216] One group of preferred compounds according to structure (IIa) arethose compounds wherein:

[0217] d, e and f are as previously defined for structure (II);

[0218] Ar⁴ is selected from the group consisting of phenyl, phenylindependently mono- or di-substituted with Y⁴, 5-10 membered heteroaryland 5-10 membered heteroaryl independently mono- or di-substituted withY⁴;

[0219] each Y⁴ is independently selected from the group consisting of—R′, —OR′, —OR″, —SR′, —SR″, —NR′R′, —NO₂, —CN, -halogen,-trihalomethyl, trihalomethoxy, —C(O)R′, —C(O)OR′, —C(O)NR′R′,—C(O)NR′OR′, —C(NR′R′)═NOR′, —NR′—C(O)R′, —SO₂R′, —SO₂R″, —NR′—SO₂—R′,—NR′—C(O)—NR′R′, tetrazol-5-yl, —NR′—C(O)—OR′, —C(NR′R′)═NR′, —S(O)—R′,—S(O)—R″, —NR′—C(S)—NR′R′;

[0220] each R′ is independently selected from the group consisting of—H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl and (C₂-C₈) alkynyl; and

[0221] each R″ is independently selected from the group consisting ofphenyl and phenyl independently mono- or di-substituted with halogen,—NR′R′, —NO₂ or —CN.

[0222] Another group of preferred compounds according to structure (IIa)are those compounds wherein d is two, e is two and/or f is zero.

[0223] Another group of preferred compounds according to structure (IIa)are those compounds wherein Ar⁴ is selected from the group consisting ofthienyl (preferably thien-2-yl), 2,1,3-benzothiadiazolyl (also known aspiazthiolyl) (preferably 2,1,3-benzothiadiazol-5-yl or piathiol-5-yl),imidazolyl (preferably imidazol-4-yl), 1,7-thiazopyrrolizinyl(preferably 1,7-thiazopyrrolizin-5-yl) and the above-describedheteroaryl groups which are independently substituted (preferablymono-substituted) with one or more Y⁴ groups. Particularly preferredcompounds according to this aspect of the invention are as follows:Compound (EG) d e f Ar⁴ 1417 2 2 0

1419 2 0

1420 2 2 0

1421 2 2 0

1423 2 2 0

1425 2 2 0

1472 2 2 0

[0224] Another group of preferred compounds according to structure (IIa)are those compounds wherein Ar⁴ is selected from the group consisting ofphenyl and phenyl independently mono-, di- or tri-substituted with Y⁴.One group of preferred compounds according to this aspect of theinvention are those compounds having the structural formula (IIa′):

[0225] or pharmaceutically acceptable salts thereof, wherein:

[0226] d, e, and f are as previously defined for structure (IIa);

[0227] R¹⁴, R¹⁵ and R¹⁶ are each independently selected from the groupconsisting of —R′, —OR′, —OR″, —SR′, —SR″, —NR′R′, —NO₂, —CN, -halogen,-trihalomethyl, trihalomethoxy, —C(O)R′, —C(O)OR′, —C(O)NR′R′,—C(O)NR′OR′, —C(NR′R′)═NOR′, —NR′—C(O)R′, —SO₂R′, —SO₂R″, —NR′—SO₂—R′,—NR′—C(O)—NR′R′, tetrazol-5-yl, and —NR′—C(O)—OR′;

[0228] each R′ is independently selected from the group consisting of—H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl and (C₂-C₈) alkynyl; and

[0229] R″ is selected from the group consisting of phenyl and phenylindependently mono-, di-substituted or tri-substituted with halogen or—CN, with the proviso that when d and e are each one, f is other thanzero.

[0230] One group of preferred compounds according to structure (IIa′)are those compounds wherein d is two, e is two and/or f is zero.

[0231] Another group of preferred compounds according to structure(IIa′) are those compounds wherein at least two of R¹⁴, R¹⁵ and R¹⁶ are—H. Still another group of preferred compounds according to structure(IIa′) are as follows: Compound (FG) d e f R¹⁴ R¹⁵ R¹⁶ 1302 2 2 0 —H —H—OMe 1407 2 2 0 —H —H —C(O)OH 1408 2 2 0 —H —C(O)OH —H 1409 2 2 0 —H —H—C(NH₂)═NOH 1411 2 2 0 —H —H —NH—C(O)Me 1414 2 2 1 —H —H —H 1415 2 2 0—H —OMe —OMe 1416 2 2 0 —H —H —O(nBu) 1418 2 2 0 —H —H

1422 2 2 0 —H —H —CF₃ 1424 2 2 0 —H —H —OCF₃ 1457 2 2 0 —H —C(NH₂)═NOH—H 1461 2 2 0 —C(NH₂)═NOH —H —H 1463 2 2 0 —H —H —SO₂Me 1466 2 2 0—SO₂Me —H —H 1469 2 2 0 —C(O)OMe —H —H

[0232] Another group of preferred compounds according to structure (II)are those compounds wherein Ar³ is thienyl and Ar⁴ is thienyl or thienylindependently substituted with one or more Y⁴. Particularly preferredcompounds according to this aspect of the invention are compounds havingthe structural formulae (IIb) and (IIb′):

[0233] or pharmaceutically acceptable salts thereof, wherein:

[0234] d, e and f are as previously defined for structure (II);

[0235] R¹⁷ is selected from the group consisting of —R′, —OR′, —OR″,—SR′, —SR″, —NR′R′, —NO₂, —CN, -halogen, -trihalomethyl, trihalomethoxy,—C(O)R′, —C(O)OR′, —C(O)NR′R′, —C(O)NR′OR′, —C(NR′R′)═NOR′, —NR′—C(O)R′,—SO₂R′, —SO₂R″, —NR′—SO₂—R′, —NR′—C(O)—NR′R′, tetrazol-5-yl, and—NR′—C(O)—OR′;

[0236] R′ is selected from the group consisting of —H, (C₁-C₈) alkyl,(C₂-C₈) alkenyl and (C₂-C₈) alkynyl; and

[0237] R″ is (C₅-C₁₀) aryl.

[0238] One group of preferred compounds according to structures (IIb)and (IIb′) are those compounds wherein d is two, e two and/or f is zero.

[0239] Another group of preferred compounds according to structures(IIb) and (IIb′) are as follows: Compound (FG) d e f R¹⁷ 1417 2 2 0 —Br1419 2 2 0

1425 2 2 0 —H 1472 2 2 0 —C(O)NHOH

[0240] Another group of preferred compounds according to structure (II)are those compounds wherein Ar³ is benzodioxole. Particularly preferredcompounds according to this aspect of the invention are compounds havingthe structural formula (IIc):

[0241] or pharmaceutically acceptable salts thereof, wherein d, e, f,and Ar⁴ are as previously defined for structure (II).

[0242] One group of preferred compounds according to structure (IIc) arethose compounds wherein:

[0243] d, e and f are as previously defined for structure (I);

[0244] Ar⁴ is selected from the group consisting of phenyl, phenylindependently mono- or di-substituted with Y⁴, 5-10 membered heteroaryland 5-10 membered heteroaryl mono- or di-substituted with Y⁴; and

[0245] Y⁴ is as previously defined for structure (II).

[0246] Another group of preferred compounds according to structure (IIc)are those compounds wherein d is two, e is one and/or f is zero.

[0247] Another group of preferred compounds according to structure (IIc)are those compounds wherein Ar⁴ is selected from the group consisting ofthienyl (preferably thien-2-yl), 2,1,3-benzothiadiazolyl (also known aspiazthiolyl) (preferably 2,1,3-benzothiadiazol-5-yl or piathiol-5-yl),imidazolyl (preferably imidazol-4-yl), 1,7-thiazopyrrolizinyl(preferably 1,7-thiazopyrrolizin-5-yl) and the above-describedheteroaryl groups which are independently mono- or di-substituted(preferably mono-substituted) with one or more Y⁴ groups. Particularlypreferred compounds of structure (IIc) according to this aspect of theinvention are as follows: Compound (EG) d e f Ar⁴ 1367 2 1 0

1361 2 1 0

1362 2 1 0

1363 2 1 0

1365 2 1 0

1371 2 1 0

1473 2 1 0

[0248] Another group of preferred compounds according to structure (IIc)are those compounds wherein Ar⁴ is selected from the group consisting ofphenyl and phenyl independently mono-, di- or tri-substituted with Y⁴.One group of preferred compounds according to this aspect of theinvention are those compounds having the structural formula (IIc′):

[0249] or pharmaceutically acceptable salts thereof, wherein:

[0250] d, e, f, R¹⁴, R¹⁵ and R¹⁶ are as previously defined for structure(IIa′).

[0251] One group of preferred compounds according to structure (IIc′)are those compounds wherein d is two, e is one and/or f is zero.

[0252] Another group of preferred compounds according to structure(IIc′) are those compounds wherein at least two of R¹⁴, R¹⁵ and R¹⁶ are—H.

[0253] Yet another group of preferred compounds according to structure(IIc′) are as follows: Compound (FG) d e f R¹⁴ R¹⁵ R¹⁶ 1273 2 1 0 —H —H—OMe 1370 2 1 0 —H —H —C(O)OH 1373 2 1 0 —H —C(O)OH —H 1369 2 1 0 —H —H—C(NH₂)═NOH 1357 2 1 0 —H —H —NH—C(O)Me 1360 2 1 0 —H —H —H 1410 2 1 0—H —OMe —OMe 1372 2 1 0 —H —H —O(nBu) 1368 2 1 0 —H —H

1364 2 1 0 —H —H —CF₃ 1366 2 1 0 —H —H —OCF₃ 1458 2 1 0 —H —C(NH₂)═NOH—H 1462 2 1 0 —C(NH₂)═NOH —H —H 1464 2 1 0 —H —H —SO₂Me 1467 2 1 0—SO₂Me —H —H 1470 2 1 0 —C(O)OMe —H —H

[0254] Still another group of preferred compounds according to structure(II) are those compounds wherein Ar³ is benzodioxole and Ar⁴ is thienylor thienyl independently substituted with one or more Y⁴. Particularlypreferred compounds according to this aspect of the invention arecompounds having the structural formulae (IId) and (IId′):

[0255] or pharmaceutically acceptable salts thereof, wherein:

[0256] d, e, f are as previously defined for structures (IIb) and(IIb′);

[0257] each R¹⁷ is independently selected from the group consisting of—R′, —OR′, —OR″, —SR′, —SR″, —NR′R′, —NO₂, —CN, -halogen,-trihalomethyl, trihalomethoxy, —C(O)R′, —C(O)OR′, —C(O)NR′R′,—C(O)NR′OR′, —C(NR′R′)═NOR′, —NR′—C(O)R′, —SO₂R′, —SO₂R″, —NR′—SO₂—R′,—NR′—C(O)—NR′R′, tetrazol-5-yl, and —NR′—C(O)—OR′;

[0258] each R′ is independently selected from the group consisting of—H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl and (C₂-C₈) alkynyl; and

[0259] R″ is selected from the group consisting of phenyl and phenylindependently mono-, di-substituted or tri-substituted with halogen or—CN.

[0260] One preferred group of compounds according to structures (IId)and (IId′) are those compounds where d is two, e is one and/or f iszero.

[0261] Another group of preferred compounds according to structures(IId) and (IId′) are as follows: Compound (FG) d e f R¹⁷ 1367 2 1 0 —Br1361 2 1 0

1371 2 1 0 —H 1473 2 1 0 —C(O)NHOH

[0262] In another embodiment, the compounds which are capable ofinhibiting C-proteinase according to the invention, and which cantherefore be used in methods to inhibit, modulate or regulate collagenproduction or maturation or to treat diseases related to, or associatedwith, unregulated collagen production or maturation are generallyN-cycloalkyl or N-heterocycloalkyl substituted arylsulfonylaminohydroxamic acids having the structural formula (III):

[0263] or pharmaceutically acceptable salts thereof, wherein:

[0264] g is an integer from 1 to 4;

[0265] h is an integer from 0 to 4;

[0266] i is an integer from 0 to 4;

[0267] Z is selected from the group consisting of (C₃-C₁₀) cycloalkyl,(C₃-C₁₀) cycloalkyl independently substituted with one or more Y⁵, 3-10membered heterocycloalkyl and 3-10 membered heterocycloalkylindependently substituted with one or more Y⁵;

[0268] Ar⁶ is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀) aryl independently substituted with one or more Y⁶, 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more Y⁶;

[0269] each Y⁵ is independently selected from the group consisting of alipophilic functional group, (C₅-C₂₀) aryl, (C₆-C₂₆) alkaryl, 5-20membered heteroaryl and 6-26 membered alk-heteroaryl;

[0270] each Y⁶ is independently selected from the group consisting of—R′, —OR′, —OR″, —SR′, —SR″, —NR′R′, —NO₂, —CN, -halogen,-trihalomethyl, trihalomethoxy, —C(O)R′, —C(O)OR′, —C(O)NR′R′,—C(O)NR′OR′, —C(NR′R′)═NOR′, —NR′—C(O)R′, —SO₂R′, —SO₂R″, —NR′—SO₂—R′,—NR′—C(O)—NR′R′, tetrazol-5-yl, —NR′—C(O)—OR′, —C(NR′R′)═NR′, —S(O)—R′,—S(O)—R″, and —NR′—C(S)—NR′R—; and

[0271] R′ and R″ are as previously defined for structure (II), with theproviso that when g and h are 1, i is 0, and Ar⁶ is phenyl, then Z isother than C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-lower alkyl, N-loweralkyl-piperazino-lower alkyl, (morpholino, thiomorpholino, piperidino,pyrrolidino, piperidyl or N-lower alkylpiperidyl)-lower alkyl.

[0272] One group of preferred compounds according to structure (III) arethose compounds wherein g is two and/or i is zero.

[0273] Another group of preferred compounds according to structure (III)are those compounds wherein:

[0274] Z is adamantyl, cyclohexyl, morpholino, tetrahydrofuranyl,piperidyl and piperidyl mono-substituted with Y⁵;

[0275] Ar⁶ is selected from the group consisting of phenyl and phenylmono-substituted with Y⁶; and

[0276] Y⁵ is —(CH₂)_(n)-phenyl, where n is an integer from 0 to 3.

[0277] Another group of preferred compounds according to structure (III)are those compounds wherein Ar⁶ is (C₁-C₆) alkoxyphenyl. Particularlypreferred compounds according to this aspect of the invention are thosecompounds having the structural formula (IIIa):

[0278] or pharmaceutically acceptable salts thereof, wherein:

[0279] g, h and Z are as previously defined for structure (III).

[0280] Particularly preferred compounds according to structure (IIIa)are as follows: Compound (FG) g h Z 1131 2 2

1306 2 1

1335 2 0

1379 2 0

1380 2 1

[0281] In another embodiment, the compounds that are capable ofinhibiting C-proteinase according to the invention, and which cantherefore be used in methods to inhibit, modulate or regulate collagenproduction or maturation or to treat diseases related to, or associatedwith, unregulated collagen production or maturation are generally N′substituted urea-arylsulfonylamino hydroxamic acids having thestructural formula (IV):

[0282] or pharmaceutically acceptable salts thereof, wherein:

[0283] j is an integer from 1 to 4;

[0284] k is an integer from 0 to 4;

[0285] Ar⁷ is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀)aryl independently substituted with one or more Y⁷, 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more Y⁷;

[0286] R¹⁸ and R¹⁹ are each independently selected from the groupconsisting of hydrogen, (C₁-C₈) alkyl, (C₂-C₈) alkenyl, (C₂-C₈) alkynyl,(C₃-C₁₀) cycloalkyl, (C₅-C₂₀) aryl, (C₅-C₂₀) substituted aryl, (C₆-C₂₆)alkaryl, (C₆-C₂₆) substituted alkaryl, 5-20 membered heteroaryl, 5-20membered substituted heteroaryl, 6-26 membered alk-heteroaryl, and 6-26membered substituted alk-heteroaryl;

[0287] each Y⁷ is independently selected from the group consisting of anelectron-donating functional group, an electron-withdrawing functionalgroup, and a lipophilic functional group.

[0288] Typical electron-donating functional groups that areindependently selected for Y⁷ in compounds of formula (IV) include, butare not limited to —Cl, —R, —OR, —SR, and —NRR; where each R isindependently —H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl or (C₂-C₉) alkynyl.Particularly preferred electron-donating groups are —Cl and —OCH₃.

[0289] Typical electron-withdrawing functional groups that areindependently selected for Y⁷ in compounds of formula (IV) include, butare not limited to —F, —NO, —NO₂, —CN, -trihalomethyl or —SO₂NHR; whereR is —H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl, (C₂-C₈) alkynyl, (C₅-C₂₀) aryl,(C₆-C₂₀) alkaryl, 5-20 membered heteroaryl and 6-26 memberedalk-heteroaryl as defined herein.

[0290] Typical lipophilic functional groups that are selected for Y⁷include, but are not limited to n-butyl, alkoxy such as butoxy, andbromo.

[0291] One group of preferred compounds according to structure (IV) arethose compounds wherein Ar⁷ is(C₅-C₂₀) aryl or (C₅-C₂₀) arylindependently substituted with one or more Y⁷ as defined in formula(IV). Particularly preferred compounds according to this aspect of theinvention are those compounds having the structural formula (IVa):

[0292] or pharmaceutically acceptable salts thereof, wherein:

[0293] j, k, R¹⁸ and R¹⁹ are as defined in formula (IV);

[0294] R²⁰, R²¹, R²² R²³, R²⁴ are independently selected from the groupconsisting of an electron-donating functional group, anelectron-withdrawing functional group, and a lipophilic functionalgroup.

[0295] Typical electron-donating functional groups that areindependently selected for compounds of formula (IVa) include, but arenot limited to —Cl, —R, —OR, —SR, —NRR, and where each R isindependently —H, (C₂-C₈) alkyl, (C₂-C₈) alkenyl or (C₂-C₈) alkynyl.Particularly preferred electron-donating groups are —Cl and —OCH₃.

[0296] Typical electron-withdrawing functional groups that areindependently selected for Y⁷ in compounds of formula (IV) include, butare not limited to —NO, —NO₂, —CN, -trihalomethyl; and —SO₂NHR; where Ris independently H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl, (C₂-C₈) alkynyl,(C₅-C₂₀) aryl, (C₆-C₂₆) alkaryl, 5-20 membered heteroaryl and 6-26membered alk-heteroaryl as defined herein.

[0297] Typical lipophilic functional groups that are selected for Y⁷include, but are not limited to n-butyl, alkoxy such as butoxy, andbromo.

[0298] Another group of preferred compounds according to structure (IV)are those compounds wherein Ar⁷ is phenyl independently substituted withone or more Y⁷ as defined in formula (IV). Particularly preferredcompounds according to this aspect of the invention are those compoundshaving the structural formula (IVb):

[0299] or pharmaceutically acceptable salts thereof, wherein:

[0300] R¹⁸ and R¹⁹ are as defined in formula (IV);

[0301] R⁵⁰, R⁵¹ and R⁵² are each independently selected from the groupconsisting of —H, —R, —OR, —SR, —NRR, —NO₂, —CN, halogen, trihalomethyl,—C(O)R, —C(O)OR, —C(O)NRR, —C(NRR)═NOR, —C(O)NROR, —SO₂NRR, and —NRSO₂R;and

[0302] each R is independently selected from the group consisting of(C₁-C₈) alkyl, (C₂-C₈) alkenyl and (C₂-C₈) alkynyl. Particularlypreferred compounds according to structure (IVb) are as follows:Compound (FG) R¹⁸ R¹⁹ R⁵⁰ R⁵¹ R⁵² 1730 4-chlorophenyl —H —OMe —H —H 1731—CH₂phenyl —H —OMe —H —H 1732 —CH₂—CH₂-phenyl —H —OMe —H —H 1733 —Me —H—OMe —H —H 1858

—H —OMe —H —H 1891 —Ph —H —OMe —H —H 1894 —CH₂-(4—fluorophenyl) —H —OMe—H —H 1895 -phenyl —Ph —OMe —H —H 1896 -4-biphenyl —H —OMe —H —H 1943

—H —H —H —OMe 1944

—H —H —OMe —H

[0303] In another embodiment, the compounds that are capable ofinhibiting C-proteinase according to the invention, and which cantherefore be used in methods to inhibit, modulate or regulate collagenproduction or maturation or to treat diseases related to, or associatedwith, unregulated collagen production or maturation are urea-hydroxamicacids having the structural formula (V):

[0304] or pharmaceutically acceptable salts thereof, wherein:

[0305] 1 is an integer from 1 to 4;

[0306] m is an integer from 0 to 4;

[0307] Ar⁸ is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀) aryl independently substituted with one or more Y⁸, 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more Y⁸;

[0308] each R²⁰ is independently selected from the group consisting ofhydrogen, (C₁-C₈) alkyl, (C₂-C₈) alkenyl, (C₂-C₈) alkynyl, (C₃-C₁₀)cycloalkyl, (C₅-C₂₀) aryl, (C₅-C₂₀) substituted aryl, (C₆-C₂₆) alkaryl,(C₆-C₂₆) substituted alkaryl, 5-20 membered heteroaryl, 5-20 memberedsubstituted heteroaryl, 6-26 membered alk-heteroaryl, and 6-26 memberedsubstituted alk-heteroaryl;

[0309] R²¹ is independently selected from the group consisting ofhydrogen, (C₁-C₈) alkyl, (C₂-C₈) alkenyl, and (C₂-C₈) alkynyl; and

[0310] each Y⁸ is independently selected from the group consisting of anelectron-donating functional group, an electron-withdrawing functionalgroup, and a lipophilic functional group.

[0311] Typical electron-donating functional groups that areindependently selected for Y⁷ in compounds of formula (V) include, butare not limited to —Cl, —R, —OR, —SR, and —NRR; where each R isindependently —H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl or (C₂-C₈) alkynyl.Particularly preferred electron-donating groups are —Cl and —OCH₃.

[0312] Typical electron-withdrawing functional groups that areindependently selected for Y⁷ in compounds of formula (V) include, butare not limited to —F, —NO, —NO₂, —CN, -trihalomethyl, —SO₂NHR; where Ris independently —H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl, (C₂-C₈) alkynyl,(C₅-C₂₀) aryl, (C₆-C₂₆) alkaryl, 5-20 membered heteroaryl and 6-26membered alk-heteroaryl as defined herein.

[0313] Typical lipophilic functional groups that are selected for Y⁷ incompounds of formula (V) include, but are not limited to n-butyl, alkoxysuch as butoxy, and bromo.

[0314] In another embodiment, the compounds that are capable ofinhibiting C-proteinase according to the invention, and which cantherefore be used in methods to inhibit, modulate or regulate collagenproduction or maturation or to treat diseases related to, or associatedwith, unregulated collagen production or maturation are benzoylsubstituted hydroxamic acids having the structural formula (VI):

[0315] or pharmaceutically acceptable salts thereof, wherein:

[0316] n is an integer from 1 to 4;

[0317] o is an integer from 0 to 4;

[0318] Ar⁹ is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀) aryl independently substituted with one or more Y⁹, 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more Y⁹; and

[0319] each R²⁵, R²⁶, R²⁷, R²⁸, R²⁹ and Y⁹ is independently selectedfrom the group consisting of an electron-donating functional group, anelectron-withdrawing functional group, and a lipophilic functionalgroup.

[0320] Typical electron-donating functional groups that areindependently selected for Y⁹in compounds of formula (VI) include, butare not limited to —Cl, —R, —OR, —SR, and —NRR, where each R isindependently —H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl or (C₂-C₈) alkynyl.Particularly preferred electron-donating groups are —Cl and —OCH₃.

[0321] Typical electron-withdrawing functional groups that areindependently selected for Y⁹ in compounds of formula (VI) include, butare not limited to —F, —NO, —NO₂, —CN, -trihalomethyl, and —SO₂NHR,where R is independently H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl, (C₂-C₈)alkynyl, (C₅-C₂₀) aryl, (C₆-C₂₆) alkaryl, 5-20 membered heteroaryl and6-26 membered alk-heteroaryl as defined herein.

[0322] Typical lipophilic functional groups that are selected for Y⁹include, but are not limited to n-butyl, alkoxy such as butoxy, andbromo.

[0323] Another group of preferred compounds according to structure (VI)are those compounds wherein Ar⁹ is phenyl independently substituted withone or more Y⁸ as defined in formula (VI). Particularly preferredcompounds according to this aspect of the invention are those compoundshaving the structural formula (VIa):

[0324] or pharmaceutically acceptable salts thereof, wherein:

[0325] R²⁵, R²⁶, R²⁷, R²⁸, R²⁹ are as defined in formula (VI).;

[0326] R³⁰, R³¹ and R³² are each independently selected from the groupconsisting of —H, —R, —OR, —SR, —NRR, —NO₂, —CN, halogen, trihalomethyl,—C(O)R, —C(O)OR, —C(O)NRR, —C(NRR)═NOR, —C(O)NROR, —SO₂NRR, and —NRSO₂R;and

[0327] each R is independently selected from the group consisting of(C₁-C₈) alkyl, (C₂-C₈) alkenyl and (C₂-C₈) alkynyl. A particularlypreferred compound according to structure (VIa) is FG 2032:

[0328] In a final embodiment, the compounds that are capable ofinhibiting C-proteinase according to the invention, and which cantherefore be used in methods to inhibit, modulate or regulate collagenproduction or maturation or to treat diseases related to, or associatedwith, unregulated collagen production or maturation are benzylsulfonylsubstituted hydroxamic acids having the structural formula (VII):

[0329] or pharmaceutically acceptable salts thereof, wherein:

[0330] p is an integer from 1 to 4;

[0331] q is an integer from 0 to 4;

[0332] Ar¹⁰ is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀) aryl independently substituted with one or more Y¹⁰, 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more Y¹⁰; and

[0333] each R³³ R³⁴, R³⁵, R³⁶,R³⁷ and Y¹⁰ is independently selected fromthe group consisting of an electron-donating functional group, anelectron-withdrawing functional group, and a lipophilic functionalgroup.

[0334] Typical electron-donating functional groups that areindependently selected for Y¹⁰ in compounds of formula (VII) include,but are not limited to —Cl, —R, —OR, —SR, —NRR, and where each R isindependently —H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl or (C₂-C₈) alkynyl.Particularly preferred electron-donating groups are —Cl and —OCH₃.

[0335] Typical electron-withdrawing functional groups that areindependently selected for Y¹⁰ in compounds of formula (VII) include,but are not limited to —F, —NO, —NO₂, —CN, -trihalomethyl, and —SO₂NHR;where R is independently H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl, (C₂-C₈)alkynyl, (C₅-C₂₀) aryl, (C₆-C₂₆) alkaryl, 5-20 membered heteroaryl and6-26 membered alk-heteroaryl as defined herein.

[0336] Typical lipophilic functional groups that are selected for Y¹⁰include, but are not limited to n-butyl, alkoxy such as butoxy, andbromo.

[0337] A group of preferred compounds according to structure (VII) arethose compounds wherein Ar¹⁰ is phenyl independently substituted withone or more Y¹⁰ as defined in formula (VII). Particularly preferredcompounds according to this aspect of the invention are those compoundshaving the structural formula (VIIa):

[0338] or pharmaceutically acceptable salts thereof, wherein:

[0339] R³³, R³⁴, R³⁵, R³⁶, R³⁷ are as defined in formula (VII);

[0340] R³⁸, R³⁹ and R⁴⁰ are independently selected from the groupconsisting of —H, —R, —OR, —SR, —NRR, —NO₂, —CN, halogen, trihalomethyl,—C(O)R, —C(O)OR, —C(O)NRR, —C(NRR)═NOR, —C(O) NROR, —SO₂NRR, and—NRSO₂R; and

[0341] each R is independently selected from the group consisting of(C₁-C₈) alkyl, (C₂-C₈) alkenyl and (C₂-C₈) alkynyl. Particularlypreferred compounds according to structure (VIIa) is FG 2033:

[0342] The chemical structural formulae referred to herein may exhibitthe phenomena of tautomerism, conformational isomerism, geometricisomerism and/or stereo isomerism. As the formulae drawings within thisspecification can only represent one of the possible tautomeric,conformational isomeric, geometric isomeric or stereo isomeric forms, itshould be understood that the invention encompasses any tautomeric,conformational isomeric, geometric isomeric or stereo isomeric formswhich exhibit biological or pharmacological activity as defined herein.

[0343] The compounds of the invention may be in the form of free acids,free bases or pharmaceutically effective acid addition or base additionsalts. Such acid addition salts can be readily prepared by treating acompound with a pharmaceutically acceptable acid. Pharmaceuticallyacceptable acids include, by way of example and not limitation,inorganic acids such as hydrohalic acids (hydrochloric, hydrobromic,etc.), sulfuric acid, nitric acid, phosphoric acid, etc.; and organicacids such as acetic acid, propanoic acid, 2-hydroxyacetic acid,2-hydroxypropanoic acid, 2-oxopropanoic acid, propandioic acid,butandioic acid, etc. Conversely, the acid addition salt can beconverted into the free base form by treatment with alkali. Appropriatebase addition salts can be readily prepared by treating a compound witha pharmaceutically acceptable base.

[0344] In addition to the above compounds and their pharmaceuticallyacceptable salts, the invention is further directed, where applicable,to solvated as well as unsolvated forms of the compounds (e.g. hydratedforms) exhibiting biological or pharmacological activity as definedherein.

[0345] 5.2 Methods of Making the Compounds

[0346] The compounds of the invention may be prepared by any processknown to be applicable to the preparation of chemical compounds.Suitable processes are well-known in the art. See e.g., Tamura et al.,1998, J. Med. Chem. 41:640-649; MacPherson et al., 1997, J. Med. Chem.40:2525-2532; and WO96/27583. Preferred processes are illustrated by therepresentative examples. Necessary starting materials may be obtainedcommercially or by standard procedures of organic chemistry.

[0347] By way of example, the compounds of the invention can beconveniently prepared by schemes (I) thru (XV) below:

[0348] In Scheme (I),

[0349] b is an integer from 0 to 4;

[0350] c is an integer from 0 to 4;

[0351] Ar¹ is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀) aryl independently substituted with one or more 5-20 memberedheteroaryl and 5-20 membered heteroaryl independently substituted withone or more Y¹;

[0352] Ar² is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀) aryl independently substituted with one or more Y², 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more Y²;

[0353] each Y¹ is independently selected from the group consisting of anelectron-donating functional group, an electron-withdrawing functionalgroup, and a lipophilic functional group;

[0354] each y² is independently selected from the group consisting of afunctional group having an acidic hydrogen, a functional group capableof participating in a hydrogen bond, a polar functional group, anelectron-withdrawing functional group, an electron-donating functionalgroup, and a lipophilic functional group; and

[0355] R is methyl or ethyl.

[0356] According to Scheme (I), methyl acrylate or ethyl acrylate 1 isadded to a solution of a primary amine 2 in ethanol. The mixture isheated to reflux (ca. 90° C.) for 20 h and then concentrated. Theresidue 3 is dissolved in methylene chloride (2.8 mL/mmol), followed bythe addition of sulfonyl chloride 4 (1 eq.) and Amberlyst (A-21) weaklybasic ion exchange resin (0.8 g/mmol). The mixture is vortexed overnightat room temperature (ca. 18 h), monitored by TLC by observing thedisappearance of sulfonyl chloride. The reaction mixture is filtered andconcentrated to yield residue 5. To 5 is added 2 equivalents of freshlyprepared neutralized NH₂OH (1 M in methanol). The mixture is vortexedovernight (monitored by TLC), concentrated, followed by work upprocedure and/or chromatographic purification to afford 6. Two work upprocedures are set up depending upon the feature of the product.

[0357] Hydrophobic compounds 6 are treated with 1 N HCl solution andextracted with ethyl acetate. The organic layer is dried over MgSO₄,filtered, and concentrated. The residue is then triturated with ether toremove undesired products which are discarded. The solid is collectedand dried in vacco.

[0358] Hydrophilic compounds 6 are triturated with ethyl acetate twice.Ethyl acetate is decanted and discarded. The residue is treated withwater, neutralized by 1 N HCl solution to pH=7-8, and extracted with10/1 ethyl acetate/methanol. The combined organic layers is washed withbrine, dried over magnesium sulfate, filtered, and concentrated. Theresidue is triturated in ether, which is discarded, and dried in vaccoto furnish the product as a white solid.

[0359] In the case that a solid product formed during the work upprocess, the solid is collected, washed with ethyl acetate and dried invacco. In the case that TLC indicates low purity of the desired product,purification is conducted using silica gel chromatography and/orrecrystallization.

[0360] In Scheme (II),

[0361] e is an integer from 0 to 4;

[0362] f is an integer from 0 to 4;

[0363] Ar³ is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀) aryl independently substituted with one or more Y³, 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more Y³;

[0364] Ar⁴ is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀) aryl independently substituted with one or more Y⁴, 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more Y⁴;

[0365] each Y³ is independently selected from the group consisting of—R′, —OR′, —SR′, —NR′R′, —NO₂, —CN, -halogen and trihalomethyl;

[0366] each Y⁴ is independently selected from the group consisting of—R′, —OR′, —OR′, —SR′, —SR′, —NR′R′, —NO₂′, —CN, -halogen,-trihalomethyl, trihalomethoxy, —C(O)R′, —C(O)OR′, —C(O)NR′R′,—C(O)NR′OR′, —C(NR′R′)═NOR′, —NR′—C(O)R′, —SO₂R′, —SO₂R″, —NR′—SO₂—R′,—NR′—C(O)—NR′R′, tetrazol-5-yl, —NR′—C(O)—OR′, —C(NR′R′)═NR′, —S(O)—R′,—S(O)—R″, —NR′—C(S)—NR′R′;

[0367] each R′ is independently selected from the group consisting of—H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl and (C₂-C₈) alkynyl;

[0368] each R″ is independently selected from the group consisting of(C₅-C₂₀) aryl and (C₅-C₂₀) aryl independently substituted with one ormore —OR′, —SR′, —NR′R′, —NO₂, —CN, halogen or trihalomethyl groups;and

[0369] R is methyl or ethyl.

[0370] According to Scheme (II), methyl acrylate or ethyl acrylate 7 isadded to a solution of a primary amine 8 in ethanol. The mixture isheated to reflux (ca. 90° C.) for 20 h and then concentrated. Theresidue 9 is dissolved in methylene chloride (2.8 mL/mmol), followed bythe addition of sulfonyl chloride 10 (1 eq.) and Amberlyst (A-21) weaklybasic ion exchange resin (0.8 g/mmol). The mixture is vortexed overnightat room temperature (ca. 18 h), monitored by TLC by observing thedisappearance of sulfonyl chloride. The reaction mixture is filtered andconcentrated to yield residue 11. To 11 is added 2 equivalents offreshly prepared neutralized NH₂OH (1 M in methanol). The mixture isvortexed overnight (monitored by TLC), concentrated, followed by a workup procedure and/or chromatographic purification to afford 12. The workup procedure used depended upon the hydrophobicity of the product:

[0371] Hydrophobic compounds 12 are treated with 1 N HCl solution andextracted with ethyl acetate. The organic layer is dried over MgSO₄,filtered, and concentrated. The residue is then triturated with ether toremove undesired products which are discarded. The solid is collectedand dried in vacco.

[0372] Hydrophilic compounds 12 are triturated with ethyl acetate twice.Ethyl acetate is decanted and discarded. The residue is treated withwater, neutralized by 1 N HCl solution to pH=7-8, and extracted with10/1 ethyl acetate/methanol. The combined organic layers is washed withbrine, dried over magnesium sulfate, filtered, and concentrated. Theresidue is triturated in ether, which is discarded, and dried in vaccoto furnish the product as a white solid.

[0373] In the case that solid product formed during work up process, thesolid is collected, washed with ethyl acetate and dried in vacco. In thecase that TLC indicates low purity of the desired product, purificationis conducted using silica gel chromatography and/or recrystallization.

[0374] In Scheme (III)

[0375] h is an integer from 0 to 4;

[0376] i is an integer from 0 to 4;

[0377] Z is selected from the group consisting of (C₃-C₁₀) cycloalkyl,(C₃-C₁₀) cycloalkyl independently substituted with one or more Y⁵, 3-10membered heterocycloalkyl and 3-10 membered heterocycloalkylindependently substituted with one or more Y⁵;

[0378] Ar⁶ is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀) aryl independently substituted with one or more Y⁶, 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more y⁶;

[0379] each Y⁵ is independently selected from the group consisting of alipophilic functional group, (C₅-C₂₀) aryl, (C₆-C₂₆) alkaryl, 5-20membered heteroaryl and 6-26 membered alk-heteroaryl;

[0380] each y⁶ is independently selected from the group consisting of—R′, —OR′, —OR′, —SR′, —SR′, —NR′R′, —NO₂, —CN, -halogen,-trihalomethyl, trihalomethoxy, —C(O)R′, —C(O)OR′, —C(O)NR′R′,—C(O)NR′OR′, —C(NR′R′)═NOR′, —NR′—C(O)R′, —SO₂R′, —SO₂R″, —NR′—SO₂—R′,—NR′—C(O)—NR′R′, tetrazol-5-yl, —NR′—C(O)—OR′, —C(NR′R′)═NR′, —S(O)—R′,—S(O)—R″, —NR′—C(S) —NR′R′;

[0381] R′ and R″ are as previously defined for Scheme (II);

[0382] and R is methyl or ethyl.

[0383] According to Scheme (III), methyl acrylate or ethyl acrylate 13is added to a solution of a primary amine 14 in ethanol. The mixture isheated to reflux (ca. 90° C.) for 20 h and then concentrated. Theresidue 15 is dissolved in methylene chloride (2.8 mL/mmol), followed bythe addition of sulfonyl chloride 16 (1 eq.) and Amberlyst (A-21) weaklybasic ion exchange resin (0.8 g/mmol). The mixture is vortexed overnightat room temperature (ca. 18 h), monitored by TLC by observing thedisappearance of sulfonyl chloride. The reaction mixture is filtered andconcentrated to yield residue 17. To 17 is added 2 equivalents offreshly prepared neutralized NH₂OH (1 M in methanol). The mixture isvortexed overnight (monitored by TLC), concentrated, followed by work upprocedure and/or chromatographic purification to afford 18. The work upprocedure used depended upon the hydrophobicity of the product:

[0384] Hydrophobic compounds 18 are treated with 1 N HCl solution andextracted with ethyl acetate. The organic layer is dried over MgSO₄,filtered, and concentrated. The residue is then triturated with ether toremove undesired products which are discarded. The solid is collectedand dried in vacco.

[0385] Hydrophilic compounds 18 are triturated with ethyl acetate twice.Ethyl acetate is decanted and discarded. The residue is treated withwater, neutralized by 1 N HCl solution is to pH=7-8, and extracted with10/1 ethyl acetate/methanol. The combined organic layers is washed withbrine, dried over magnesium sulfate, filtered, and concentrated. Theresidue is triturated in ether, which is discarded, and dried in vaccoto furnish the product as a white solid.

[0386] In the case that solid product formed during work up process, thesolid is collected, washed with ethyl acetate and dried in vacco. In thecase that TLC indicates low purity of the desired product, purificationis conducted using silica gel chromatography and/or recrystallization.

[0387] In Scheme (IV),

[0388] a is an integer from 1 to 4;

[0389] b is an integer from 0 to 4;

[0390] c is an integer from 0 to 4;

[0391] Ar¹ is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀) aryl independently substituted with one or more Y¹, 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more Y¹;

[0392] Ar² is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀) aryl independently substituted with one or more Y², 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more y²;

[0393] each Y¹ is independently selected from the group consisting of anelectron-donating functional group, an electron-accepting functionalgroup, and a lipophilic functional group;

[0394] each Y² is independently selected from the group consisting of afunctional group having an acidic hydrogen, a functional group capableof participating in a hydrogen bond, a polar functional group, anelectron-withdrawing functional group, an electron-donating functionalgroup, and a lipophilic functional group;

[0395] R is methyl or ethyl; and

[0396] X is chloro or bromo.

[0397] According to Scheme (IV), a primary amine 19 is dissolved inmethylene chloride, followed by the addition of sulfonyl chloride 20 andAmberlyst weakly basic ion exchange resin to yield compound 21. Compound21 is dissolved in dry DMF and stirred under argon. To this mixture isadded sodium hydride 60% suspended in mineral oil and the resultingmixture stirred. To this mixture is added compound 22 to yield compound23 after silica gel chromatography. To compound 23 is added freshlyprepared NH₂OH (1 M in methanol). The mixture is stirred to affordcompound 24. Depending on the chemical properties of compound 24, it isworked up as follows.

[0398] Hydrophobic compounds 24 are treated with a HCl solution andextracted with ethyl acetate. The organic layer is dried over MgSO₄,filtered, and concentrated. The residue is then triturated with ether toremove undesired products which are discarded. The solid is collectedand dried in vacco.

[0399] Hydrophilic compounds 24 are triturated with ethyl acetate twice.Ethyl acetate is decanted and discarded. The residue is treated withwater, neutralized by 1 N HCl solution to pH=7-8, and extracted with10/1 ethyl acetate/methanol. The combined organic layers is washed withbrine, dried over magnesium sulfate, filtered, and concentrated. Theresidue is triturated in ether, which is discarded, and dried in vaccoto furnish the product as a white solid.

[0400] In Scheme (V),

[0401] d is an integer from 1 to 4;

[0402] e is an integer from 0 to 4;

[0403] f is an integer from 0 to 4;

[0404] Ar³ is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀) aryl independently substituted with one or more Y³, 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more Y³;

[0405] Ar⁴ is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀) aryl independently substituted with one or more Y⁴, 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more Y⁴;

[0406] each Y³ is independently selected from the group consisting of—R′, —OR′, —SR′, —NR′R′, —NO₂, —CN, -halogen and trihalomethyl;

[0407] each Y⁴ is independently selected from the group consisting of—R′, —OR′, —OR′, —SR′, —SR′, —NR′R′, —NO₂, —CN, -halogen,-trihalomethyl, trihalomethoxy, —C(O)R′, —C(O)OR′, —C(O)NR′R′,—C(O)NR′OR′, —C(NR′R′)═NOR′, —NR′—C(O)R′, —SO₂R′, —SO₂R″, —NR′—SO₂—R′,—NR′—C(O)—NR′R′, tetrazol-5-yl, —NR′—C(O)—OR′, —C(NR′R′)═NR′, —S(O)—R′,—S(O)—R″, —NR′—C(S)—NR′R′;

[0408] each R′ is independently selected from the group consisting of—H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl and (C₂-C₈) alkynyl;

[0409] each R″ is independently selected from the group consisting of(C₅-C₂₀) aryl and (C₅-C₂₀) aryl independently substituted with one ormore —OR′, —SR′, —NR′R′, —NO₂, —CN, halogen or trihalomethyl groups;

[0410] R is methyl or ethyl; and

[0411] X is chloro or bromo.

[0412] According to Scheme (V), a primary amine 25 is dissolved inmethylene chloride, followed by the addition of sulfonyl chloride 26 andAmberlyst weakly basic ion exchange resin to yield compound 27. Compound27 is dissolved in dry DMF and stirred under argon. To this mixture isadded sodium hydride 60% suspended in mineral oil and the resultingmixture stirred. To this mixture is added compound 28 to yield compound29 after silica gel chromatography. To compound 29 is added freshlyprepared NH₂OH (1 M in methanol). The mixture is stirred to affordcompound 30. Depending on the chemical properties of compound 30, it isworked up as follows:

[0413] Hydrophobic compounds 30 are treated with a HCl solution andextracted with ethyl acetate. The organic layer is dried over MgSO₄,filtered, and concentrated. The residue is then triturated with ether toremove undesired products which are discarded. The solid is collectedand dried in vacco.

[0414] Hydrophilic compounds 30 are triturated with ethyl acetate twice.Ethyl acetate is decanted and discarded. The residue is treated withwater, neutralized by 1 N HCl solution to pH=7-8, and extracted with10/1 ethyl acetate/methanol. The combined organic layers is washed withbrine, dried over magnesium sulfate, filtered, and concentrated. Theresidue is triturated in ether, which is discarded, and dried in vaccoto furnish the product as a white solid.

[0415] In Scheme (VI),

[0416] g is an integer from 1 to 4;

[0417] h is an integer from 0 to 4;

[0418] i is an integer from 0 to 4;

[0419] Z is selected from the group consisting of (C₃-C₁₀) cycloalkyl,(C₃-C₁₀) cycloalkyl independently substituted with one or more Y⁵, 3-10membered heterocycloalkyl and 3-10 membered heterocycloalkylindependently substituted with one or more Y⁵;

[0420] Ar⁶ is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀) aryl independently substituted with one or more Y⁶, 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more Y⁶;

[0421] each Y⁵ is independently selected from the group consisting of alipophilic functional group, (C₅-C₂₀) aryl, (C₆-C₂₆) alkaryl, 5-20membered heteroaryl and 6-26 membered alk-heteroaryl;

[0422] each Y⁶ is independently selected from the group consisting of—R′, —OR′, —OR″, —SR′, —SR″, —NR′R′, —NO₂, —CN, -halogen,-trihalomethyl, trihalomethoxy, —C(O)R′, —C(O)OR′, —C(O)NR′R′,—C(O)NR′OR′, —C(NR′R′)═NOR′, —NR′—C(O)R′, —SO₂R′, —SO₂R″, —NR′—SO—R′,—NR′—C(O)—NR′R′, tetrazol-5-yl, —NR′—C(O)—OR′, —C(NR′R′)═NR′, —S(O)—R′,—S(O)—R″, —NR′—C(S)—NR′R′;

[0423] each R′ is independently selected from the group consisting of—H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl and (C₂-C₈) alkynyl;

[0424] each R″ is independently selected from the group consisting of(C₅-C₂₀) aryl and (C₅-C₂₀) aryl independently substituted with one ormore —OR′, —SR′, —NR′R′, —NO₂, —CN, halogen or trihalomethyl groups;

[0425] R is methyl or ethyl; and

[0426] X is chloro or bromo.

[0427] According to Scheme (VI), a primary amine 31 is dissolved inmethylene chloride, followed by the addition of sulfonyl chloride 32 andAmberlyst weakly basic ion exchange resin to yield compound 33. Compound33 is dissolved in dry DMF and stirred under argon. To this mixture isadded sodium hydride 60% suspended in mineral oil and the resultingmixture stirred. To this mixture is added compound 34 to yield compound35 after silica gel chromatography. To compound 35 is added freshlyprepared NH₂OH (1 M in methanol). The mixture is stirred to affordcompound 36. Depending on the chemical properties of compound 36, it isworked up as follows.

[0428] Hydrophobic compounds 36 are treated with a HCl solution andextracted with ethyl acetate. The organic layer is dried over MgSO₄₁filtered, and concentrated. The residue is then triturated with ether toremove undesired products which are discarded. The solid is collectedand dried in vacco.

[0429] Hydrophilic compounds, 36 are triturated with ethyl acetatetwice. Ethyl acetate is decanted and discarded. The residue is treatedwith water, neutralized by 1 N HCl solution to pH 7-8, and extractedwith 10/1 ethyl acetate/methanol. The combined organic layers is washedwith brine, dried over magnesium sulfate, filtered, and concentrated.The residue is triturated in ether, which is discarded, and dried invacco to furnish the product as a white solid.

[0430] In Scheme (VII),

[0431] a is an integer from 1 to 2;

[0432] b is an integer from 0 to 4;

[0433] c is an integer from 0 to 4;

[0434] Ar¹ is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀) aryl independently substituted with one or more Y¹, 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more Y¹;

[0435] Ar² is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀) aryl independently substituted with one or more Y², 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more Y²;

[0436] each Y¹ is independently selected from the group consisting of anelectron-donating functional group, an electron-withdrawing functionalgroup, and a lipophilic functional group;

[0437] each Y² is independently selected from the group consisting of afunctional group having an acidic hydrogen, a functional group capableof participating in a hydrogen bond, a polar functional group, anelectron-withdrawing functional group, an electron-donating functionalgroup, and a lipophilic functional group; and

[0438] R is methyl or ethyl.

[0439] According to Scheme (VII), to a solution of compound 37 inanhydrous methylene chloride at room temperature is added triethyl amineand compound 38. After the mixture is stirred, sodiumtriacetoxyborohydride is added and the reaction mixture is stirred foradditional period of time to yield compound 39. To compound 39 is addedcompound 40 and triethyl amine. The resulting mixture is stirred andthen quenched with citric acid yielding compound 41. To compound 41 inmethanol is added freshly prepared NH₂OH solution. The mixture isstirred and concentrated to yield compound 42.

[0440] In Scheme (VIII),

[0441] d is an integer from 1 to 4;

[0442] e is an integer from 0 to 4;

[0443] f is an integer from 0 to 4;

[0444] Ar³ is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀) aryl independently substituted with one or more Y³, 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more Y³;

[0445] Ar⁴ is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀) aryl independently substituted with one or more Y⁴, 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more Y⁴;

[0446] each Y³ is independently selected from the group consisting of—R′, —OR′, —SR′, —NR′R′, —NO₂, —CN, -halogen and trihalomethyl;

[0447] each Y⁴ is independently selected from the group consisting of—R′, —OR′, —OR″, —SR′, —SR″, —NR′R′, —NO₂, —CN, -halogen,-trihalomethyl, trihalomethoxy, —C(O)R′, —C(O)OR′, —C(O)NR′R′,—C(O)NR′OR′, —C(NR′R′)═NOR′, —NR′—C(O)R′, —SO₂R′, —SO₂R″, —NR′—SO₂—R′,—NR′—C(O)—NR′R′, tetrazol-5-yl, —NR′—C(O)—OR′, —C(NR′R′)═NR′, —S(O)—R′,—S(O)—R″, —NR′—C(S)—NR′R′;

[0448] each R′ is independently selected from the group consisting of—H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl and (C₂-C₈) alkynyl;

[0449] each R″ is independently selected from the group consisting of(C₅-C₂₀) aryl and (C₅-C₂₀) aryl independently substituted with one ormore —OR′, —SR′, —NR′R′, —NO₂, —CN, halogen or trihalomethyl groups; and

[0450] R is methyl or ethyl.

[0451] According to Scheme (VIII), to a solution of compound 43 inanhydrous methylene chloride at room temperature is added triethyl amineand compound 44. After the mixture is stirred, sodiumtriacetoxyborohydride is added and the reaction mixture is stirred foradditional period of time to yield compound 45. To compound 45 is addedcompound 46 and triethyl amine. The resulting mixture is stirred andthen quenched with citric acid yielding compound 47. To compound 47 inmethanol is added freshly prepared NH₂OH solution. The mixture isstirred and concentrated to yield compound 48.

[0452] In scheme (IX),

[0453] g is an integer from 1 to 4;

[0454] h is an integer from 0 to 4;

[0455] i is an integer from 0 to 4;

[0456] Z is selected from the group consisting of (C₃-C₁₀) cycloalkyl,(C₃-C₁₀) cycloalkyl independently substituted with one or more Y⁵, 3-10membered heterocycloalkyl and 3-10 membered heterocycloalkylindependently substituted with one or more Y⁵;

[0457] Ar⁶ is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀) aryl independently substituted with one or more Y⁵, 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more Y⁶;

[0458] each Y⁵ is independently selected from the group consisting of alipophilic functional group, (C₅-C₂₀) aryl, (C₆-C₂₆) alkaryl, 5-20membered heteroaryl and 6-26 membered alk-heteroaryl;

[0459] each Y⁶ is independently selected from the group consisting of—R′, —OR′, —OR″, —SR′, —SR″, —NR′R′, —NO₂, —CN, -halogen,-trihalomethyl, trihalomethoxy, —C(O)R′, —C(O)OR′, —C(O)NR′R′,—C(O)NR′OR′, —C(NR′R′)═NOR′, —NR′—C(O)R′, —SO₂R′, —SO₂R″, —NR′—SO₂—R′,—NR′—C(O)—NR′R′, tetrazol-5-yl, —NR′—C(O)—OR′, —C(NR′R′)═NR′, —S(O)—R′,—S(O)—R″, and —NR′—C(S)—NR′R′;

[0460] each R′ is independently selected from the group consisting of—H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl and (C₂-C₈) alkynyl;

[0461] each R″ is independently selected from the group consisting of(C₅-C₂₀) aryl and (C₅-C₂₀) aryl independently substituted with one ormore —OR′, —SR′, —NR′R′, —NO₂, —CN, halogen or trihalomethyl groups; and

[0462] R is methyl or ethyl.

[0463] According to scheme (IX), to a solution of compound 49 inanhydrous methylene chloride at room temperature is added triethyl amineand compound 50. After the mixture is stirred, sodiumtriacetoxyborohydride is added and the reaction mixture is stirred foradditional period of time to yield compound 51. To compound 51 is addedcompound 52 and triethyl amine. The resulting mixture is stirred andthen quenched with citric acid yielding compound 53. To compound 53 inmethanol is added freshly prepared NH₂OH solution. The mixture isstirred and concentrated to yield compound 54.

[0464] In Scheme (X),

[0465] k is an integer from 0 to 4;

[0466] Ar⁷ is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀) aryl independently substituted with one or more Y⁷, 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more Y⁷

[0467] R¹⁸ and R¹⁹ are independently selected from the group consistingof hydrogen, (C₁-C₈) alkyl, (C₂-C₈) alkenyl, (C₂-C₈) alkynyl, (C₃-C₁₀)cycloalkyl, (C₅-C₂₀) aryl, (C₅-C₂₀) substituted aryl, (C₆-C₂₆) alkaryl,(C₅-C₂₆) substituted alkaryl, 6-20 membered heteroaryl, 5-20 memberedsubstituted heteroaryl, 6-26 membered alk-heteroaryl, and 6-26 memberedsubstituted alk-heteroaryl; and

[0468] each Y⁷ is independently selected from the group consisting of anelectron-donating functional group, an electron-withdrawing functionalgroup, and a lipophilic functional group.

[0469] Typical electron-donating functional groups that areindependently selected for Y⁷ in compounds of formula (IV) include, butare not limited to —Cl, —R, —OR, —SR, —NRR, and where each R isindependently —H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl or (C₂-C₈) alkynyl.Particularly preferred electron-donating groups are —Cl and —OCH₃.

[0470] Typical electron-withdrawing functional groups that areindependently selected for Y⁷ in compounds of formula (IV) include, butare not limited to —F, —NO, —NO₂, —CN, -trihalomethyl, —SO₂NHR; where Ris independently H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl, (C₂-C₈) alkynyl,(C₅-C₂₀) aryl, (C₆-C₂₆) alkaryl, 5-20 membered heteroaryl and 6-26membered alk-heteroaryl as defined herein.

[0471] Typical lipophilic functional groups that are selected for Y⁷include, but are not limited to n-butyl, alkoxy such as butoxy, andbromo; and

[0472] R is methyl or ethyl.

[0473] According to Scheme (X), methyl acrylate or ethyl acrylate 55 isadded to a solution of a primary amine 56 in ethanol. The mixture isheated to reflux (ca. 90° C.) for 20 h and then concentrated. Theresidue 57 is dissolved in methylene chloride, followed by the additionof 4-(3-substituted-ureido)benzenesulfonyl chloride 58 (1 eq.) andAmberlyst (A-21) weakly basic ion exchange resin (0.8 g/mmol). Themixture is vortexed overnight at room temperature (ca. 18 h), monitoredby TLC by observing the disappearance of sulfonyl chloride. The reactionmixture is filtered and concentrated to yield residue 59. To 59 is added2 equivalents of freshly prepared neutralized NH₂OH (1 M in methanol).The mixture is vortexed overnight (monitored by TLC), concentrated,followed by work up procedure and/or chromatographic purification toafford 60. Two work up procedures are set up depending upon the featureof the product.

[0474] Hydrophobic compounds 60 are treated with 1 N HCl solution andextracted with ethyl acetate. The organic layer is dried over MgSO₄,filtered, and concentrated. The residue is then triturated with ether toremove undesired products which are discarded. The solid is collectedand dried in vacco.

[0475] Hydrophilic compounds 60 are triturated with ethyl acetate twice.Ethyl acetate is decanted and discarded. The residue is treated withwater, neutralized by 1 N HCl solution to pH=7-8, and extracted with10/1 ethyl acetate/methanol. The combined organic layers is washed withbrine, dried over magnesium sulfate, filtered, and concentrated. Theresidue is triturated in ether, which is discarded, and dried in vaccoto furnish the product as a white solid.

[0476] In the case that solid product formed during work up process, thesolid is collected, washed with ethyl acetate and dried in vacco. In thecase that TLC indicates low purity of the desired product, purificationis conducted using silica gel chromatography and/or recrystallization.

[0477] Compound 58 is prepared by the following method: To a solution ofprimary or secondary amine 61 (0.5 mmol) in THF (1 mL) at 0° C. wasadded 4-(chlorosulfonyl)phenyl isocyanate 62 (0.5 mmol). After stirringat 0° C. for 2 h, the mixture was concentrated to afford4-(3-substituted-ureido)benzenesulfonyl chloride 58.

[0478] In Scheme (XI),

[0479] j is an integer from 1 to 4;

[0480] k is an integer from 0 to 4;

[0481] Ar⁷ is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀) aryl independently substituted with one or more Y⁷, 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more Y⁷;

[0482] R¹⁸ and R¹⁹ are independently selected from the group consistingof hydrogen, (C₁-C₈) alkyl, (C₂-C₈) alkenyl, (C₅-C₂₀) alkynyl, (C₃-C₁₀)cycloalkyl, (C₅-C₂₀) aryl, (C₅-C₂₀) substituted aryl, (C₆-C₂₆) alkaryl,(C₆-C₂₆) substituted alkaryl, 5-20 membered heteroaryl, 5-20 memberedsubstituted heteroaryl, 6-26 membered alk-heteroaryl, and 6-26 memberedsubstituted alk-heteroaryl;

[0483] each Y⁷ is independently selected from the group consisting of anelectron-donating functional group, an electron-withdrawing functionalgroup, and a lipophilic functional group; and

[0484] R is methyl or ethyl.

[0485] Typical electron-donating functional groups that areindependently selected for Y⁷ in compounds of formula (IV) include, butare not limited to —Cl, —R, —OR, —SR, and —NRR; where each R isindependently H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl or (C₂-C₈) alkynyl.Particularly preferred electron-donating groups are —Cl and —OCH₃.

[0486] Typical electron-withdrawing functional groups that areindependently selected for Y⁷ in compounds of formula (IV) include, butare not limited to —F, —NO, —NO₂, —CN, -trihalomethyl, and —SO₂NHR;where R is independently H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl, (C₂-C₈)alkynyl, (C₅-C₂₀) aryl, (C₆-C₂₆) alkaryl, 5-20 membered heteroaryl and6-26 membered alk-heteroaryl as defined herein.

[0487] Typical lipophilic functional groups that are selected for Y⁷include, but are not limited to n-butyl, alkoxy such as butoxy, andbromo.

[0488] According to Scheme (XI), to a solution of compound 63 inanhydrous methylene chloride at room temperature is added triethyl amineand compound 64. After the mixture is stirred, sodiumtriacetoxyborohydride is added and the reaction mixture is stirred foradditional period of time to yield compound 65. To compound 65 is addedcompound 66 and triethyl amine. The resulting mixture is stirred andthen quenched with citric acid yielding compound 67. To compound 67 inmethanol is added freshly prepared NH₂OH solution. The mixture isstirred and concentrated to yield compound 68.

[0489] Compound 66 is prepared by the following method. To a solution ofprimary or secondary amine 69 (0.5 mmol) in THF (1 mL) at 0° C. wasadded 4-(chlorosulfonyl)phenyl isocyanate 70 (0.5 mmol). After stirringat 0° C. for 2 h, the mixture was concentrated to afford4-(3-substituted-ureido)benzenesulfonyl chloride 66.

[0490] In Scheme (XII),

[0491] j is an integer from 1 to 4;

[0492] k is an integer from 0 to 4;

[0493] Ar⁷ is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀) aryl independently substituted with one or more Y⁷, 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more Y⁷;

[0494] R¹⁸ and R¹⁹ are independently selected from the group consistingof hydrogen, (C₁-C₈) alkyl, (C₂-C₈) alkenyl, (C₂-C₈) alkynyl, (C₃-C₁₀)cycloalkyl, (C₅-C₂₀) aryl, (C₅-C₂₀) substituted aryl, (C₆-C₂₆) alkaryl,(C₆-C₂₆) substituted alkaryl, 5-20 membered heteroaryl, 5-20 memberedsubstituted heteroaryl, 6-26 membered alk-heteroaryl, and 6-26 memberedsubstituted alk-heteroaryl;

[0495] each Y⁷ is independently selected from the group consisting of anelectron-donating functional group, an electron-withdrawing functionalgroup, and a lipophilic functional group;

[0496] R is methyl or ethyl; and

[0497] X is chloro or bromo.

[0498] Typical electron-donating functional groups that areindependently selected for Y⁷ in compounds of formula (XII) include, butare not limited to —Cl, —R, —OR, —SR, and —NRR; where each R isindependently H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl or (C₂-C₈) alkynyl.Particularly preferred electron-donating groups are —Cl and —OCH₃.

[0499] Typical electron-withdrawing functional groups that areindependently selected for Y⁷ in compounds of formula (XII) include, butare not limited to —F, —NO, —NO₂, —CN, -trihalomethyl, and —SO₂NR; whereR is independently H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl, (C₂-C₈) alkynyl,(C₅-C₂₀) aryl, (C₆-C₂₆) alkaryl, 5-20 membered heteroaryl and 6-26membered alk-heteroaryl as defined herein.

[0500] Typical lipophilic functional groups that are selected for Y⁷include, but are not limited to n-butyl, alkoxy such as butoxy, andbromo.

[0501] According to Scheme (XII), a primary amine 71 is dissolved inmethylene chloride, followed by the addition of benzylsulfonyl chloride72 and Amberlyst weakly basic ion exchange resin to yield compound 73.Compound 73 is dissolved in dry DMF and stirred under argon. To thismixture is added sodium hydride 60% suspended in mineral oil and theresulting mixture stirred. To this mixture is added compound 74 to yieldcompound 75 after silica gel chromatography. To compound 75 is addedfreshly prepared NH₂OH (1 M in methanol). The mixture is stirred toafford compound 76. Depending on the chemical properties of compound 76,it is worked up as follows:

[0502] Hydrophobic compounds 76 are treated with a HCl solution andextracted with ethyl acetate. The organic layer is dried over MgSO₄,filtered, and concentrated. The residue is then triturated with ether toremove undesired products which are discarded. The solid is collectedand dried in vacco.

[0503] Hydrophilic compounds 76 are triturated with ethyl acetate twice.Ethyl acetate is decanted and discarded. The residue is treated withwater, neutralized by 1 N HCl solution to pH=7-8, and extracted with10/1 ethyl acetate/methanol. The combined organic layers is washed withbrine, dried over magnesium sulfate, filtered, and concentrated. Theresidue is triturated in ether, which is discarded, and dried in vaccoto furnish the product as a white solid.

[0504] Preparation of (compound 72)4-(3—Substituted-ureido)-benzenesulfonyl Chloride: To a solution ofprimary or secondary amine 77 (0.5 mmol) in THF (1 mL) at 0° C. is added4-(chlorosulfonyl)phenyl isocyanate 78 (0.5 mmol). After stirring at 0°C. for 2 h, the mixture was concentrated to afford4-(3-substituted-ureido)benzenesulfonyl chloride 72.

[0505] In Scheme (XIII),

[0506] n is an integer from 1 to 4;

[0507] o is an integer from 0 to 4;

[0508] Ar⁹ is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀) aryl independently substituted with one or more Y⁹, 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more Y⁹;

[0509] each R²⁵, R^(26,) R²⁷, R²⁸, R²⁹ and Y⁹ is independently selectedfrom the group consisting of an electron-donating functional group, anelectron-withdrawing functional group, and a lipophilic functionalgroup; and

[0510] X is chloro or bromo.

[0511] Typical electron-donating functional groups that areindependently selected for Y⁹ include, but are not limited to —Cl, —R,—OR, —SR, and —NRR; where each R is independently H, (C₁-C₈) alkyl,(C₂-C₈) alkenyl or (C₂-C₈) alkynyl. Particularly preferredelectron-donating groups are Cl and —OCH₃.

[0512] Typical electron-withdrawing functional groups that areindependently selected for Y⁹include, but are not limited to —F, —NO,—NO₂, —CN, -trihalomethyl, and —SO₂NHR; where R is independently H,(C₁-C₈) alkyl, (C₂-C₈) alkenyl, (C₂-C₈) alkynyl, (C₅-C₂₀) aryl, (C₆-C₂₆)alkaryl, 5-20 membered heteroaryl and 6-26 membered alk-heteroaryl asdefined herein.

[0513] Typical lipophilic functional groups that are selected for Y⁹include, but are not limited to n-butyl, alkoxy such as butoxy, andhalogen.

[0514] According to scheme (XIII), to a solution of 79 in 5:1methanol/ethyl acetate (4.2 mL/mmol) is added by portion palladium (10%)in charcoal solid (10% w/w), followed by ammonium formate (4 eq.). Theresulting mixture is refluxed for 6 hours and filtered through a pad ofcelite. Filtrate is concentrated and partitioned between ethyl acetateand water. Organic layer is washed with brine, dried over sodiumsulfate, filtered and concentrated to give 80. To a solution of 80 inacetonitrile (7.8 mL/mmol) is added the corresponding electrophile (1.1eq.) substituted benzoyl halide 81 followed by triethyl amine (2 eq.).The mixture is stirred at room temperature for 5 hours and thenpartitioned between methylene chloride and 0.1 N hydrochloric acidaqueous solution. The acid layer is extracted with methylene chloride.Combined organic layers are washed with brine, dried over magnesiumsulfate, filtered, and concentrated. The residue is then treated with 10equivalents of freshly prepared neutralized NH₂OH (1 M in methanol). Themixture is stirred at room temperature for 5 hours and concentrated toyield residue 82. Residue 82 is partitioned between 10:1 ethylacetate/methanol and 1 N hydrochloric acid aqueous solution. The organiclayer is washed with brine, dried over magnesium sulfate, filtered, andconcentrated to give the corresponding hydroxamic acid 83.

[0515] In Scheme (XIV),

[0516] p is an integer from 1 to 4;

[0517] q is an integer from 0 to 4;

[0518] Ar¹⁰ is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀) aryl independently substituted with one or more Y⁸, 5-20membered heteroaryl and 5-20 membered heteroaryl independentlysubstituted with one or more Y¹⁰;

[0519] each R³³, R³⁴, R³⁵, R³⁶, R³⁷ and Y¹⁰ is independently selectedfrom the group consisting of an electron-donating functional group, anelectron-withdrawing functional group, and a lipophilic functionalgroup; and

[0520] X is chloro or bromo.

[0521] Typical electron-donating functional groups that areindependently selected for Y¹⁰ include, but are not limited to —Cl, —R,—OR, —SR, and —NRR, where each R is independently H, (C₁-C₈) alkyl,(C₂-C₈) alkenyl or (C₂-C₈) alkynyl. Particularly preferredelectron-donating groups are —Cl and —OCH₃.

[0522] Typical electron-withdrawing functional groups that areindependently selected for Y¹⁰ include, but are not limited to —F, —NO,—NO₂, —CN, -trihalomethyl, and —SO₂NHR; where R is independently H,(C₁-C₈) alkyl, (C₂-C₈) alkenyl, (C₂-C₈) alkynyl, (C₅-C₂₀) aryl, (C₆-C₂₆)alkaryl, 5-20 membered heteroaryl and 6-26 membered alk-heteroaryl asdefined herein.

[0523] Typical lipophilic functional groups that are selected for Y¹⁰include, but are not limited to n-butyl, alkoxy such as butoxy, andbromo.

[0524] According to scheme (XIV), to a solution of 84 in 5:1methanol/ethyl acetate (4.2 mL/mmol) is added by portion palladium (10%)in charcoal solid (10% w/w), followed by ammonium formate (4 eq.). Theresulting mixture is refluxed for 6 hours and filtered through a pad ofcelite. Filtrate is concentrated and partitioned between ethyl acetateand water. Organic layer is then washed with brine, dried over sodiumsulfate, filtered and concentrated to give 85. To a solution of 85 inacetonitrile (7.8 mL/mmol) is added the corresponding electrophile (1.1eq.) substituted benzenesulfonyl halide 86 followed by triethyl amine (2eq.). The mixture is stirred at room temperature for 5 hours and thenpartitioned between methylene chloride and 0.1 N hydrochloric acidaqueous solution. The acid layer is extracted with methylene chloride.Combined organic layers are washed with brine, dried over magnesiumsulfate, filtered, and concentrated to yield 87. Residue 87 is thentreated with 10 equivalents of freshly prepared neutralized NH₂OH (1 Min methanol). The mixture is stirred at room temperature for 5 hours andconcentrated to yield residue 88. Residue 88 is partitioned between 10:1ethyl acetate/methanol and 1 N hydrochloric acid aqueous solution. Theorganic layer is washed with brine, dried over magnesium sulfate,filtered, and concentrated to give isolated hydroxamic acid 88.

[0525] In Scheme (XV),

[0526] 1 is an integer from 1 to 4;

[0527] m is an integer from 0 to 4;

[0528] Ar⁸ is selected from the group consisting of (C₅-C₂₀) aryl,(C₅-C₂₀) aryl independently substituted with one or more Y⁸, 5-20membered heteroaryl, and 5-20 membered heteroaryl independentlysubstituted with one or more Y⁸;

[0529] R²⁰ is independently selected from the group consisting of H,(C₁-C₈) alkyl, (C₂-C₈) alkenyl, and (C₂-C₈) alkynyl; and

[0530] R²¹ is selected from the group consisting of hydrogen, (C₁-C₈)alkyl, (C₂-C₈) alkenyl, (C₂-C₈) alkynyl, (C₃-C₁₀) cycloalkyl, (C₅-C₂₀)aryl, (C₅-C₂₀) substituted aryl, (C₆-C₂₆) alkaryl, (C₆-C₂₆) substitutedalkaryl, 5-20 membered heteroaryl, 5-20 membered substituted heteroaryl,6-26 membered alk-heteroaryl, and 6-26 membered substitutedalk-heteroaryl.

[0531] According to Scheme (XV) to a solution of 89 in 5:1methanol/ethyl acetate (4.2 mL/mmol) is added by portion palladium (10%)in charcoal solid (10% w/w), followed by ammonium formate (4 eq.). Theresulting mixture is refluxed for 6 hours and filtered through a pad ofcelite. Filtrate is concentrated and partitioned between ethyl acetateand water. Organic layer is washed with brine, dried over sodiumsulfate, filtered and concentrated to give 90. To a solution of 90 isadded aldehyde 91 followed by triethyl amine to yield compound 92. Tocompound 92 is added compound 93 to yield compound 94. Compound 94 istreated with 10 equivalents of freshly prepared NH₂OH (1 M in methanol).The mixture is stirred at room temperature for 5 hours and concentratedto yield residue 95.

[0532] 5.3 Biological and Pharmacological Activity

[0533] An individual compound's relevant activity and potency as aninhibitor of C-proteinase, to regulate or modulate collagen productionor maturation and/or to treat disorders associated with unregulatedcollagen production may be determined using available techniques.

[0534] Typically, active compounds of the invention will inhibit 50% ofthe activity of C-proteinase at concentrations in the range of 100micromolar (μM) or less (i.e., those compounds exhibiting an IC₅₀ of 100μM or less) using standard biochemical assays (Dickson, 1953, Biochem.J. 55:170-171; Knight et al., 1992, FEBS 296:263-266). Those of skill inthe art will appreciate that compounds exhibiting lower inhibitoryconcentrations (IC₅₀s) are generally preferred for pharmacologicalapplications; thus, preferably active compounds will exhibit IC₅₀s thatare less than 10 μM, more preferably less than 1 μM, even morepreferably less than 100 nanomolar (nM) and even more preferably lessthan about 10 nM or 1 nM. However, as compounds which exhibit IC₅₀s inthe millimolar (mM) range can provide consequential pharmacologicalbenefits, compounds which exhibit IC₅₀s as high as 1 mM to 10 mM areconsidered to possess biological or pharmacological activity.

[0535] Alternatively, an in vitro procollagen assay may be used todetermine the level of activity and effect of different compounds of thepresent invention on C-proteinase activity. In the procollagen assay,about 125 μg radiolabeled (¹⁴C) procollagen is added to 10 units/mL ofchicken C-proteinase in a solution of 0.1 M Tris-HCl, 0.1 M NaCl, 0.02%Brij-35, and 5 mM CaCl₂ in a total volume of 10 μl. The reaction isallowed to proceed for 15 minutes at 35° C. and is stopped with one-halfvolume of 3×stop/loading buffer (30 mM EDTA, 30% glycerol, 6% SDS,0.006% Bromophenol-blue). Subsequently, the samples are heated to 100°C. for 4 minutes, and resolved by SDS-PAGE (Novex) using 6%polyacryleamide gels. The protein bands are detected by autoradiography.The amount of enzyme activity is based on the disappearance of the bandcorresponding to uncleaved procollagen. The IC₅₀ of inhibitors can bedetermined by plotting the % activity versus inhibitor concentration andestimating the inhibitor concentration which results in 50% activity.

[0536] 5.4 Indications

[0537] Disorders associated with unregulated collagen production ormaturation can be treated with the compounds and compositions of thepresent invention. While not intending to be bound by any particulartheory, it is believed that when administered to an animal subject,including a human, the compounds of the invention inhibit C-proteinasein vivo, thereby effectively modulating, regulating or inhibitingcollagen production or maturation. As a consequence, the compounds areable to treat or prevent disorders associated with unregulated collagenproduction or maturation.

[0538] Collagen-related disorders which can be treated or preventedaccording to the invention include pathological fibrosis or scarring,such as endocardial sclerosis, idiopathic interstitial fibrosis,interstitial pulmonary fibrosis, perimuscular fibrosis, Symmers'fibrosis, pericentral fibrosis, hepatitis, dermatofibroma, billarycirrhosis, alcoholic cirrhosis, acute pulmonary fibrosis, idiopathicpulmonary fibrosis, acute respiratory distress syndrome, kidneyfibrosis/glomerulonephritis, kidney fibrosis/diabetic nephropathy,scleroderma/systemic, scleroderma/local, keloids, hypertrophic scars,severe joint adhesions/arthritis, myelofibrosis, corneal scarring,cystic fibrosis, muscular dystrophy (duchenne's), cardiac fibrosis,muscular fibrosis/retinal separation, esophageal stricture, payronlesdisease. Further, fibrotic disorders may be induced or initiated bysurgery such as scar revision/plastic surgeries, glaucoma, cataractfibrosis, corneal scarring, joint adhesions, graft vs. host disease,tendon surgery, nerve entrapment, dupuytren's contracture, OB/GYNadhesions/fibrosis, pelvic adhesions, peridural fibrosis, restenosis.Still further fibrotic disorders may be induced by chemotherapy,including, for example lung fibrosis and the like.

[0539] 5.5 Pharmaceutical Formulations And Routes Of Administration

[0540] The compounds described herein, or pharmaceutically acceptableaddition salts or hydrates thereof, can be delivered to a subject,including a human, using a wide variety of routes or modes ofadministration. Suitable routes of administration include, but are notlimited to, inhalation, transdermal, oral, rectal, transmucosal,intestinal and parenteral administration, including intramuscular,subcutaneous and intravenous injections.

[0541] The compounds described herein, or pharmaceutically acceptablesalts and/or hydrates thereof, may be administered singly, incombination with other compounds of the invention, and/or in cocktailscombined with other therapeutic agents. Of course, the choice oftherapeutic agents that can be co-administered with the compounds of theinvention will depend, in part, on the condition being treated.

[0542] For example, the compounds of the invention can be administeredin cocktails containing agents used to treat the pain and other symptomsand side effects commonly associated with fibrotic disorders. Thecompounds can also be administered in cocktails containing other agentsthat are commonly used to treat fibrotic disorders.

[0543] The active compound(s) may be administered per se or in the formof a pharmaceutical composition containing the active compound(s) andone or more pharmaceutically acceptable carriers, excipients ordiluents. Administered compounds may be enantiomerically pure, or may bemixtures of enantiomers. Pharmaceutical compositions for use inaccordance with the present invention may be formulated in conventionalmanner using one or more physiologically acceptable carriers comprisingexcipients and auxiliaries which facilitate processing of the activecompounds into preparations which can be used pharmaceutically. Properformulation is dependent upon the route of administration chosen.

[0544] For injection, the agents of the invention may be formulated inaqueous solutions, preferably in physiologically compatible buffers suchas Hanks's solution, Ringer's solution, or physiological saline buffer.For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants aregenerally known in the art.

[0545] For oral administration, the compounds can be formulated bycombining the active compound(s) with pharmaceutically acceptablecarriers well known in the art. Such carriers enable the compounds ofthe invention to be formulated as tablets, pills, dragees, capsules,liquids, gels, syrups, slurries, suspensions and the like, for oralingestion by a patient to be treated. Pharmaceutical preparations fororal use can be obtained solid excipient, optionally grinding aresulting mixture, and processing the mixture of granules, after addingsuitable auxiliaries, if desired, to obtain tablets or dragee cores.Suitable excipients are, in particular, fillers such as sugars,including lactose, sucrose, mannitol, or sorbitol; cellulosepreparations such as, for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/orpolyvinylpyrrolidone (PVP). If desired, disintegrating agents may beadded, such as the cross-linked polyvinyl pyrrolidone, agar, or alginicacid or a salt thereof such as sodium alginate.

[0546] Dragee cores are provided with suitable coatings. For thispurpose, concentrated sugar solutions may be used, which may optionallycontain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel,polyethylene glycol, and/or titanium dioxide, lacquer solutions, andsuitable organic solvents or solvent mixtures. Dyestuffs or pigments maybe added to the tablets or dragee coatings for identification or tocharacterize different combinations of active compound doses.

[0547] Pharmaceutical preparations which can be used orally includepush-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for suchadministration.

[0548] For buccal administration, the compositions may take the form oftablets or lozenges formulated in conventional manner.

[0549] For administration by inhalation, the compounds for use accordingto the present invention are conveniently delivered in the form of anaerosol spray presentation from pressurized packs or a nebulizer, withthe use of a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of e.g. gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

[0550] The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form, e.g., in ampules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents.

[0551] Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

[0552] Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

[0553] The compounds may also be formulated in rectal compositions suchas suppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.

[0554] In addition to the formulations previously described, thecompounds may also be formulated as a depot preparation. Such longacting formulations may be administered by implantation ortranscutaneous delivery (for example subcutaneously or intramuscularly),intramuscular injection or a transdermal patch. Thus, for example, thecompounds may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

[0555] The pharmaceutical compositions also may comprise suitable solidor gel phase carriers or excipients. Examples of such carriers orexcipients include but are not limited to calcium carbonate, calciumphosphate, various sugars, starches, cellulose derivatives, gelatin, andpolymers such as polyethylene glycols.

[0556] 5.5.1 Effective Dosage.

[0557] Pharmaceutical compositions suitable for use in the presentinvention include compositions wherein the active ingredients arecontained in an effective amount to achieve its intended purpose. Morespecifically, a therapeutically effective amount means an amounteffective to prevent development of or to alleviate the existingsymptoms of the subject being treated. Determination-of the effectiveamounts is well within the capability of those skilled in the art,especially in light of the detailed disclosure provided herein.

[0558] For any compound used in the method of the invention, thetherapeutically effective dose can be estimated initially from cellculture assays. For example, a dose can be formulated in animal modelsto achieve a circulating concentration range that includes the IC₅₀ asdetermined in cell culture (i.e., the concentration of the test compoundwhich achieves a half-maximal inhibition of the C-proteinase activity).Such information can be used to more accurately determine useful dosesin humans.

[0559] A therapeutically effective dose refers to that amount of thecompound that results in amelioration of symptoms or a prolongation ofsurvival in a patient. Toxicity and therapeutic efficacy of suchcompounds can be determined by standard pharmaceutical procedures incell cultures or experimental animals, e.g., for determining the LD₅₀(the dose lethal to 50% of the population) and the ED₅₀ (the dosetherapeutically effective in 50% of the population). The dose ratiobetween toxic and therapeutic effects is the therapeutic index and itcan be expressed as the ratio between LD₅₀ and ED₅₀. Compounds whichexhibit high therapeutic indices are preferred. The data obtained fromthese cell culture assays and animal studies can be used in formulatinga range of dosage for use in human. The dosage of such compounds liespreferably within a range of circulating concentrations that include theED₅₀ with little or no toxicity. The dosage may vary within this rangedepending upon the dosage form employed and the route of administrationutilized. The exact formulation, route of administration and dosage canbe chosen by the individual physician in view of the patient'scondition. See, e.g., Fingl et al., 1975, in “The Pharmacological Basisof Therapeutics”, Ch. 1 p.1.

[0560] Dosage amount and interval may be adjusted individually toprovide plasma levels of the active moiety which are sufficient tomaintain the C-proteinase inhibiting effects, or minimal effectiveconcentration (MEC). The MEC will vary for each compound but can beestimated from in vitro data; for example, the concentration necessaryto achieve 50-90% inhibition of the C-proteinase using the assaysdescribed herein. Dosages necessary to achieve the MEC will depend onindividual characteristics and route of administration. However, HPLCassays or bioassays can be used to determine plasma concentrations.

[0561] Dosage intervals can also be determined using MEC value.Compounds should be administered using a regimen which maintains plasmalevels above the MEC for 10-90% of the time, preferably between 30-90%and most preferably between 50-90%.

[0562] In cases of local administration or selective uptake, theeffective local concentration of the drug may not be related to plasmaconcentration.

[0563] The amount of composition administered will, of course, bedependent on the subject being treated, on the subject's weight, theseverity of the affliction, the manner of administration and thejudgment of the prescribing physician.

[0564] 5.5.2 Packaging

[0565] The compositions may, if desired, be presented in a pack ordispenser device which may contain one or more unit dosage formscontaining the active ingredient. The pack may, for example, comprisemetal or plastic foil, such as a blister pack. The pack or dispenserdevice may be accompanied by instructions for administration.Compositions comprising a compound of the invention formulated in acompatible pharmaceutical carrier may also be prepared, placed in anappropriate container, and labelled for treatment of an indicatedcondition. Suitable conditions indicated on the label may includetreatment of arthritis or any other fibrotic disorder.

6. EXAMPLE Compound Syntheses

[0566] The compounds of the present invention may be synthesizedaccording to known techniques. The following represent preferred methodsfor synthesizing certain compounds of the invention.

[0567] 6.1 SYNTHESIS OFN-Hydroxy-3-[(benzyl)-(4-methoxybenzenesulfonyl)-amino]-propionamide (FG121)

[0568] 6.1.1 Ethyl3-[(benzyl)-(4-methoxybenzenesulfonyl)-amino]-propionate

[0569] Ethyl acrylate (1.05 g; 10 mmol) and benzylamine (1.10 g; 10mmol) were dissolved in absolute ethanol and stirred 18 h at roomtemperature. The ethanol was removed under reduced pressure and theresulting oil dissolved CH₂Cl₂ (20 mL). p-Methoxybenzenesulfonylchloride (2.10 g; 10 mmol) and triethylamine (1.05 g; 10 mmol) wereadded, and the resulting solution stirred at room temperature 5 h. Thereaction was diluted with CH₂Cl₂ (30 mL) and washed with 1 N HCl (2×50mL) and the aqueous layers back-extracted with fresh CH₂Cl₂ (50 mL). Theorganic layers were combined, dried over MgSO₄₁ filtered and evaporated.Preparative HPLC purification, eluting with a mixture of ethylacetate/hexanes (35:65) gave 3.36 g (89%) of the title compound as apale yellow oil. 300 MHz ¹H-NMR (CDCl₃): δ1.18 (t, 3H), 2.42 (m, 2H),3.38 (m, 2H), 3.89 (s, 3H), 4.02 (m, 2H), 4.32 (s, 2H), 7.00 (m, 2H),7.30 (m, 5H), 7.79 (m, 2H).

[0570] 6.1.2N-Hydroxy-3-[(benzyl)-(4-methoxybenzenesulfonyl)-amino]-propionamide

[0571] Freshly prepared hydroxylamine reagent (20 mL; 20 mmol) was addedto ethyl 3-[(benzyl)-(4-methoxybenzenesulfonyl)-amino]-propionate (3.30g; 8.8 mmol) and the resulting mixture stirred for 18 h at roomtemperature. The mixture was poured into 1 N HCl (100 mL) and extractedwith CH₂Cl₂ (2×100 mL). The combined extracts were washed with saturatedaqueous NaCl (1×100 mL), dried over MgSO₄, and evaporated under reducedpressure to give a crude gum. Trituration with diethyl ether afforded2.33 g (68%) of the title compound as an off-white solid. 300 MHz ¹H-NMR(DMSO-d₆): δ2.06 (m, 2H), 3.25 (m, 2H), 3.87 (s, 3H), 4.33 (s, 2H), 7.16(d, 2H), 7.20-7.42 (m, 5H), 7.80 (d, 2H), 8.70 (bs, 1H), 10.38 (s, 1 H).

[0572] 6.2 SYNTHESIS OF N-BENZYL-N-p-METHOXYBENZENESULFONYL-G-AMINOBUTYRYL HYDROXAMIC ACID (FG 122)

[0573] 6.2.1 N-Benzyl p-methoxybenzenesulfonamide

[0574] Benzylamine (3.75 g; 35 mmol), p-methoxybenzenesulfonyl chloride(6.20 g; 30 mmol), and triethylamine (3.20 g; 31 mmol) were dissolved inCH₂Cl₂ (50 mL) and the resulting solution stirred 20 h at roomtemperature. The solution was washed with 0.5 N HCl (2×50 mL) and theaqueous layers back-extracted with additional CH₂Cl₂ (50 mL). Thecombined organic layers were dried over MgSO₄, filtered, and evaporatedto give 7.05 g (85%) of the title compound as a white solid. ¹H-NMR(CDCl₃): δ3.88 (s, 3H), 4.12 (d, 2H), 4.92(t, 1H), 6.97 (d, 2H),7.18-7.30 (m, 5H), 7.80 (d, 2H).

[0575] 6.2.2 Ethyl N-Benzyl-p-methoxybenzenesulfonyl-γ-Aminobutyrate

[0576] N-Benzyl p-methoxybenzenesulfonamide (2.77 g; 10 mmol) wasdissolved in dry DMF (35 mL) and stirred under argon. Sodium hydride,60% in mineral oil (0.55 g; 14 mmol), was added and the resultingmixture stirred at room temperature for 0.5 h. Ethyl 4-bromobutyrate(2.95 g; 15 mmol) and sodium iodide (250 mg) were added successively andthe reaction heated to 90° C. for 6 h. After cooling to roomtemperature, the mixture was poured into diethyl ether (100 mL) andextracted with water (2×100 mL). The organic layer was dried over MgSO₄,filtered and evaporated to an oil. Preparative HPLC purification,eluting with a mixture of ethyl acetate/hexanes (35:65) gave 3.62 g(93%) of the title compound as an oil.

[0577]¹H-NMR (CDCl₃): δ1.20 (t, 3H), 1.65 (m, 2H), 2.16 (t, 2H), 3.14(m, 2H), 3.88 (s, 3H), 4.05 (m, 2H), 4.30 (s, 2H), 6.90 (m, 2H), 7.29(m, 5H), 7.77 (m, 2H).

[0578] 6.2.3 N-Benzyl-N-p-Methoxybenzenesulfonyl-γ-AminobutyrylHydroxamic Acid

[0579] Freshly prepared hydroxylamine reagent (20 mL; 20 mmol) was addedto ethyl N-phenyl-N-p-methoxybenzenesulfonyl-β-alaninate (3.55 g; 9.1mmol) and the resulting mixture stirred for 18 h at room temperature.The mixture was poured into 1 N HCl (100 mL) and extracted with CH₂Cl₂(2×100 mL). The combined extracts were washed with saturated aqueousNaCl (1×100 mL), dried over MgSO₄, and evaporated under reduced pressureto give a crude gum. Trituration with diethyl ether afforded 1.83 g(55%) of the title compound as a tan solid.

[0580]¹H-NMR (DMSO-d₆): δ1.46 (m, 2H), 1.77 (t, 2H) 3.03 (t, 2H), 3.86(s, 3H), 4.28 (s, 2H), 7.12 (d, 2H), 7.38 (m, 5H), 7.80 (d, 2H), 8.66(s, 1H), 10.22 (s, 1H).

[0581] 6.3 SYNTHESIS OF N-PHENYL-N-p-METHOXYBENZENE SULFONYL-GLYCINE

[0582] HYDROXAMIC ACID (FG 123)

[0583] 6.3.1 N-phenyl-N-p-Methoxybenzenesulfonyl-Glycinate

[0584] N-Phenyl p-methoxybenzenesulfonamide aniline (2.80 g; 30 mmol),p-methoxybenzenesulfonyl chloride (6.20 g; 30 mmol), and triethylamine(3.20 g; 31 mmol) were dissolved in CH₂Cl₂ (50 mL) and the resultingsolution stirred 18 h at room temperature. The solution was washed with0.5 N HCl (2×50 mL) and the aqueous layers back-extracted withadditional CH₂Cl₂ (50 mL). The combined organic layers were dried overMgSO₄, filtered and evaporated to give 6.66 g (84%) of the titlecompound as a thick oil that solidified upon standing.

[0585]¹H-NMR (CDCl₃): δ3.79 (s, 3H), 6.87 (d, 2H), 7.10 (d, 2H), 7.21(m, 3H), 7.75 (m, 2H).

[0586] 6.3.2 Ethyl N-Phenyl-N-p-Methoxybenzenesulfonyl-Glycinate

[0587] N-Phenyl p-methoxybenzenesulfonamide (2.63 g; 10 mmol) wasdissolved in dry THF (50 mL) and stirred under argon. Sodium hydride,60% in mineral oil (0.55 g; 14 mmol), was added and the resultingmixture stirred at room temperature for 0.5 h. Ethyl bromoacetate (2.50g; 15 mmol) and sodium iodide (200 mg) were added successively and thereaction stirred at room temperature for 72 h. The mixture was pouredinto diethyl ether (100 mL) and extracted with water (2×100 mL). Theorganic layer was dried over MgSO₄, filtered, and evaporated to asemi-solid. Preparative HPLC purification, eluting with a mixture ofethyl acetate/hexanes (35:65) gave 2.80 g (80%) of the title compound asa light yellow solid.

[0588]¹H-NMR (CDCl₃): δ1.22 (t, 3H), 3.86 (s, 3H), 4.12 (m, 2H), 4.40(s, 2H), 6.89 (m, 2H), 7.17-7.32 (m, 5H), 7.61 (d, 2H).

[0589] 6.3.3 N-Phenyl-N-p-Methoxybenzenesulfonyl-Glycine Hydroxamic Acid

[0590] Freshly prepared hydroxylamine reagent (16 mL; 16 mmol) was addedto ethyl N-phenyl-N-p-methoxybenzenesulfonyl-glycinate (2.80 g; 8.0mmol) and the resulting mixture stirred for 6 h at room temperature. Themixture was poured into 1 N HCl (100 mL) and extracted with CH₂Cl₂(2×100 mL). The combined extracts were washed with saturated aqueousNaCl (1×100 mL), dried over MgSO₄, and evaporated under reduced pressureto give crude product. Trituration with diethyl ether afforded 1.75 g(65%) of the title compound as a white solid.

[0591]¹H-NMR (DMSO-d₆): δ3.83 (s, 3H), 4.13 (s, 2H), 7.03-7.15 (2m, 4H),7.30 (m, 3H), 7.54 (d, 2H), 8.89 (bs, 1H), 10.60 (s, 1 H).

[0592] 6.4 SYNTHESIS OFN-Hydroxy-3-[(phenyl)-(4-methoxybenzenesulfonyl)-amino]-propionamide (FG124).

[0593] 6.4.1 Ethyl 3-phenylamino-propionate

[0594] Ethyl acrylate (2.05 g; 20 mmol) and aniline (1.85 g; 20 mmol)were added to a solution of concentrated HCl (1.5 mL) in absoluteethanol (20 mL) and the resulting mixture refluxed 20 h. The reactionwas cooled to room temperature and then poured into 1 N NaOH (100 mL)and extracted with ethyl acetate (2×100 mL). The combined organic layerswere washed with water (2×100 mL), dried over MgSO₄, filtered, andevaporated to give 2.85 g (80%) of the title compound as a light amberoil. 300 MHz ¹H-NMR (CDCl₃): δ1.27 (t, 3H), 2.61 (t, 2H), 3.46 (t, 2H),4.16 (q, 2H), 6.63 (d, 2H), 6.72 (m, 1H), 7.17 (m, 2H).

[0595] 6.4.2 Ethyl3-[(phenyl)-(4-methoxybenzenesulfonyl)-amino]-propionate

[0596] The crude oil of ethyl 3-phenylamino-propionate (1.78; 10 mmol)and p-methoxybenzenesulfonyl chloride (2.10 g; mmol) were dissolved inCH₂Cl₂ (20 mL). Triethylamine (1.05 g; 10 mmol) was added and theresulting mixture stirred at room temperature overnight. The reactionwas diluted with CH₂Cl₂ (30 mL) and washed with 1 N HCl (2×50 mL) andthe aqueous layers back-extracted with fresh CH₂Cl₂ (50 mL). The organiclayers were combined, dried over MgSO₄, filtered and evaporated.Preparative HPLC purification, eluting with ethyl acetate/hexanes(35:65) gave 3.34 g (92%) of the title compound as a light yellow oil.300 MHz ¹H-NMR (CDCl₃): δ1.19 (t, 3H), 2.53 (m, 2H), 3.84 (m, 2H), 3.86(s, 3H), 4.05 (m, 2H), 6.91 (m, 2H), 7.03 (m, 2H), 7.29 (m, 3H), 7.53(m, 2H).

[0597] 6.4.3N-Hydroxy-3-[(phenyl)-(4-methoxybenzenesulfonyl)-amino]-propionamide

[0598] Freshly prepared hydroxylamine reagent (20 mL; 20 mmol) was addedto ethyl 3-[(phenyl)-(4-methoxy-benzene-sulfonyl)-amino]-propionate(3.30 g; 9.1 mmol) and the resulting mixture stirred for 18 h at roomtemperature. The mixture was poured into 1 N HCl (100 mL) and extractedwith CH₂Cl₂ (2×100 mL). The combined extracts were washed with saturatedaqueous NaCl (1×100 mL), dried over MgSO₄, and evaporated under reducedpressure to give a crude gum. Trituration with diethyl ether afforded2.14 g (68%) of the title compound as an off-white solid. 300 MHz ¹H-NMR(DMSO-d₆): δ2.12 (t, 2H), 3.74 (t, 2H), 3.86 (s, 3H), 7.03 (d, 2H), 7.08(d, 2H), 7.32 (m, 3H), 7.47 (d, 2H), 8.74 (s, 1H), 10.35 (s, 1 H).

[0599] 6.5 SYNTHESIS OF N-PHENYL-N-p-METHOXYBENZENESULFONYL-G-AMINOBUTYRYL HYDROXAMIC ACID (FG 125)

[0600] 6.5.1 Ethyl N-Phenyl-N-p-Methoxybenzenesulfonyl-γ-Aminobutyrate

[0601] N-Phenyl p-methoxybenzenesulfonamide (2.63 g; 10 mmol) wasdissolved in dry DMF (35 mL) and stirred under argon. Sodium hydride,60% in mineral oil (0.55 g; 14 mmol), was added and the resultingmixture stirred at room temperature for 0.5 h. Ethyl 4- bromobutyrate(2.95 g; 15 mmol) and sodium iodide (250 mg) were added successively andthe reaction heated to 90° C. for 24 h. After cooling to roomtemperature, the mixture was poured into diethyl ether (100 mL) andextracted with water (2×100 mL). The organic layer was dried over MgSO₄,filtered and evaporated to a solid. Preparative HPLC purification,eluting with a mixture of ethyl acetate/hexanes (35:65) gave 3.56 g(91%) of the title compound as a white solid.

[0602]¹H-NMR (CDCl₃): δ1.22 (t, 3H), 1.73 (m, 2H), 2.39 (t, 2H), 3.59(t, 2H), 3.86 (s, 3H), 4.19 (m, 2H), 6.91 (m, 2H), 7.05 (m, 2H), 7.31(m, 3H), 7.49 (m, 2H).

[0603] 6.5.2 N-Phenyl-N-p-Methoxybenzenesulfonyl-γ-AminobutyrylHydroxamic Acid

[0604] Freshly prepared hydroxylamine reagent (20 mL; 20 mmol) was addedto ethyl N-phenyl-N-p-methoxybenzenesulfonyl-b-alaninate (3.50 g; 9.0mmol) and the resulting mixture stirred for 18 h at room temperature.The mixture was poured into 1 N HCl (100 mL) and extracted with CH₂Cl₂(2×100 mL). The combined extracts were washed with saturated aqueousNaCl (1×100 mL), dried over MgSO₄, and evaporated under reduced pressureto give a crude gum. Trituration with diethyl ether afforded 2.25 g(69%) of the title compound as an off-white solid.

[0605]¹H-NMR (DMSO-d₆): δ2.12 (t, 2H), 3.74 (t, 2H), 3.86 (s, 3H), 7.03(d, 2H), 7.08 (d, 2H), 7.32 (m, 3H), 7.47 (d, 2H), 8.74 (s, 1H), 10.35(s, 1 H).

[0606] 6.6 SYNTHESIS OFN-Hydroxy-3-[(phenethyl)-(4-methoxybenzenesulfonyl)-amino]-propionamide(FG 126).

[0607] 6.6.1 Ethyl3-[(phenethyl)-(4-methoxybenzenesulfonyl)-amino]-propionate

[0608] Ethyl acrylate (1.05 g; 10 mmol) and phenethylamine (1.21 g; 10mmol) were dissolved in absolute ethanol and stirred 16 h at roomtemperature. The ethanol was removed under reduced pressure and theresulting oil dissolved CH₂Cl₂ (20 mL). p-Methoxybenzenesulfonylchloride (2.10 g; 10 mmol) and triethylamine (1.05 g; 10 mmol) wereadded, and the resulting solution stirred at room temperature 20 h. Thereaction was diluted with CH₂Cl₂ (30 mL) and washed with 1 N HCl (2×50mL) and the aqueous layers back-extracted with fresh CH₂Cl₂ (50 mL). Theorganic layers were combined, dried over MgSO₄, filtered and evaporated.Preparative HPLC purification, eluting with a mixture of ethylacetate/hexanes (35:65) gave 3.56 g (91%) of the title compound as apale yellow oil. 300 MHz ¹H-NMR (CDCl₃): δ1.26 (t, 3H), 2.58 (m, 2H),2.86 (m, 2H), 3.34 (m, 2H), 3.44 (m, 2H), 3.86 (s, 3H), 4.13 (m, 2H),6.95 (m, 2H), 7.15-7.32 (m, 5H), 7.73 (m, 2H).

[0609] 6.6.2N-Hydroxy-3-[(phenethyl)-(4-methoxybenzenesulfonyl)-amino]-propionamide

[0610] Freshly prepared hydroxylamine reagent (20 mL; 20 mmol) was addedto ethyl 3-[(phenethyl)-(4-methoxybenzenesulfonyl)-amino]-propionate(3.30 g; 9.1 mmol) and the resulting mixture stirred for 18 h at roomtemperature. The mixture was poured into 1 N HCl (100 mL) and extractedwith CH₂Cl₂ (2×100 mL). The combined extracts were washed with saturatedaqueous NaCl (1×100 mL), dried over MgSO₄, and evaporated under reducedpressure to give a crude gum. Trituration with diethyl ether afforded2.23 g (65%) of the title compound as an off-white solid. 300 MHz ¹H-NMR(DMSO-d₆): δ2.23 (t, 2H), 2.74 (m, 2H), 3.23 (m, 2H), 3.34 (m, 2H), 3.83(s, 3H), 7.11 (d, 2H), 7.15-7.34 (m, 5H), 7.72 (d, 2H), 8.78 (s, 1H),10.50 (s, 1 H).

[0611] 6.7 SYNTHESIS OFN-(2-Phenyl)ethyl-N-4-methoxybenzenesulfonyl-glycine Hydroxamic Acid (FG128).

[0612] 6.7.1Ethyl-N-(2-phenyl)ethyl-N-4-methoxybenzenesulfonyl-glycinate

[0613] Glycine ethyl ester hydrochloride (1.40 g; 10 mmol),phenylacetaldehyde (1.32 g; 10 mmol), and glacial acetic acid were addedto methanol (20 mL) and the resulting solution cooled to 0° C. underargon. After 5 min, sodium cyanoborohydride (0.65 g; 10 mmol) was addedin one portion. The reaction was stirred at 0° C. for 2 h and thenstirred 16 h at room temperature. The reaction was quenched with theaddition of 1 N HCl (30 mL) and the resulting mixture stirred for anadditional 1 h. After the removal of methanol under reduced pressure,the remaining aqueous mixture was cooled in an ice bath and carefullybasified to pH 10 with 45% (w/w) aqueous KOH, and then extracted withEtOAc (2×50 mL). The combined extracts were washed with solutions ofwater (50 mL) and saturated aqueous NaCl (50 mL), dried over MgSO₄, andevaporated to an oil. The crude material, p-methoxybenzenesulfonylchloride (2.10 g; 10 mmol), and triethylamine (1.05 g; 10 mmol) weredissolved in CH₂Cl₂ (20 mL)and the resulting solution stirred at roomtemperature for 6 h. The reaction was diluted with CH₂Cl₂ (30 mL) andwashed with 1 N HCl (2×50 mL) and the aqueous layers back-extracted withfresh CH₂Cl₂ (50 mL). The organic layers were combined, dried overMgSO₄, filtered and evaporated. Preparative HPLC purification, elutingwith ethyl acetate/hexanes (35:65) gave 2.25 g (55%) of the titlecompound as a light yellow oil. ¹H-NMR (300 MHz, CDCl₃) δ7.78 (m, 2H),7.13-7.32 (m, 5H), 6.95 (m, 2H), 4.09 (m, 2H), 3.99 (s, 2H), 3.86 (s,3H), 3.47 (m, 2H), 2.88 (m, 2H), 1.20 (t, 3H),

[0614] 6.7.2 N-(2-Phenyl)ethyl-N-p-methoxybenzenesulfonyl-glycinehydroxamic acid

[0615] Freshly prepared hydroxylamine reagent (12 mL; 12 mmol) was addedto ethyl N-(2-phenyl)ethyl-N-p-methoxybenzenesulfonyl-glycinate (2.25 g;5.5 mmol) and the resulting mixture stirred for 6 h at room temperature.The mixture was poured into 1 N HCl (100 mL) and extracted with CH₂Cl₂(2×100 mL). The combined extracts were washed with saturated aqueousNaCl (1×100 mL), dried over MgSO₄, filtered, and evaporated underreduced pressure to give crude product. Trituration with diethyl etherafforded 1.50 g (75%) of the title compound as a white solid. ¹H-NMR(300 MHz, DMSO-d₆) δ10.66 (s, 1H), 8.95 (br s, 1H), 7.75 (d, 2H),7.10-7.30 (m, 5H), 7.08 (d, 2H), 3.84 (s, 3H), 3.74 (s, 2H), 3.30 (m,2H), 2.76 (m, 2H).

[0616] 6.8 SYNTHESIS OFN-(2-PHENYL)ETHYL-N-p-METHOXYBENZENESULFONYL-G-AMINOBUTYRYL HYDROXAMICACID (FG 134)

[0617] 6.8.1 N-(2-Phenyl)ethyl p-Methoxybenzenesulfonamide

[0618] Phenethylamine (4.25 g; 35 mmol), p-methoxybenzene sulfonylchloride (6.20 g; 30 mmol), and triethylamine (3.32 g; 32 mmol) weredissolved in CH₂Cl₂ (50 mL) and the resulting solution stirred 20 h atroom temperature. The solution was washed with 0.5 N HCl (2×50 mL) andthe aqueous layers back-extracted with additional CH₂Cl₂ (50 mL). Thecombined organic layers were dried over MgSO₄, filtered and evaporatedto give 7.51 g (86%) of a thick, pale yellow oil.

[0619]¹H-NMR (CDCl₃): δ2.77 (t, 2H), 3.20 (q, 2H), 3.88 (s, 3H), 4.60(t, 1H), 6.96 (d, 2H), 7.05-7.30 (m, 5H), 7.75 (d, 2H)

[0620] 6.8.2 EthylN-(2-Phenyl)Ethyl-N-p-Methoxybenzenesulfonyl-γ-Aminobutyrate

[0621] N-(2-Phenyl) ethyl p-methoxybenzenesulfonamide (2.95 g; 10 mmol)was dissolved in dry DMF (35 mL) and stirred under argon. Sodiumhydride, 60% in mineral oil (0.55 g; 14 mmol), was added and theresulting mixture stirred at room temperature for 0.5 h. Ethyl4-bromobutyrate (2.95 g; 15 mmol) and sodium iodide (250 mg) were addedsuccessively and the reaction heated to 90° C. for 6 h. After cooling toroom temperature, the mixture was poured into diethyl ether (100 mL) andextracted with water (2×100 mL). The organic layer was dried over MgSO₄,filtered and evaporated to an oil. Preparative HPLC purification,eluting with a mixture of ethyl acetate/hexanes (35:65) gave 3.72 g(92%) of the title compound as an oil.

[0622]¹H-NMR (CDCl₃): δ1.26 (t, 3H), 1.85 (m, 2H), 2.33 (t, 2H), 2.86(m, 2H), 3.18 (m, 2H), 3.32 (m, 2H), 3.86 (s, 3H), 4.13 (m, 2H), 6.95(m, 2H), 7.15-7.32 (m, 5H), 7.73 (m, 2H).

[0623] 6.8.3 N-(2-Phenyl)Ethyl-N-p-Methoxybenzenesulfonyl-γ-AminobutyrylHydroxamic Acid

[0624] Freshly prepared hydroxylamine reagent (20 mL; 20 mmol) was addedto ethyl N-(2-phenyl)ethyl-N-p-methoxybenzene sulfonyl-β- alaninate(3.65 g; 9.1 mmol) and the resulting mixture stirred for 18 h at roomtemperature. The mixture was poured into 1 N HCl (100 mL) and extractedwith CH₂Cl₂ (2×100 mL). The combined extracts were washed with saturatedaqueous NaCl (1×100 mL), dried over MgSO₄, and evaporated under reducedpressure to give a crude gum. Trituration with diethyl ether afforded2.54 g (71%) of the title compound as an oil.

[0625]¹H-NMR (DMSO-d₆): δ1.68 (m, 2 H), 1.96 (t, 2 H), 2.77 (t, 2 H),3.11 (t, 2 H), 3.29 (t, 2 H), 3.83 (s, 3 H), 7.26-7.08 (m, 7 H), 7.72(d, 2 H), 8.69 (s, 1 H), 10.23 (s, 1 H).

[0626] 6.9 SYNTHESIS OFN-4-METHOXYPHENYL-N-4-METHOXYBENZENESULFONYL-GLYCINE HYDROXAMIC ACID (FG202)

[0627] 6.9.1 EthylN-4-Methoxyphenyl-N-4-Methoxybenzenesulfonyl-Glycinate

[0628] N-4-Methoxyphenyl 4-methoxybenzenesulfonamide (1.46 g; 5.00 mmol)was dissolved in dry DMF (25 mL) and stirred under argon. Sodiumhydride, 60% in mineral oil (224 mg; 7.0 mmol), was added and themixture stirred at room temperature for 15 min. Ethyl bromoacetate (1.25g; 7.5 mmol) and a catalytic amount of sodium iodide were added and theresulting mixture heated at 90° C. overnight. The reaction was pouredinto diethyl ether (50 mL) and washed with water (2×50 mL). The organiclayer was dried over MgSO₄, filtered, and evaporated to an oil.Preparative HPLC purification, eluting with a mixture of ethylacetate/hexanes (35:65), gave 1.75 g (92%) of the title compound as apale yellow oil.

[0629]¹H-NMR (CDCl₃): δ1.22 (t, 3H), 3.76 (s, 3H), 3.86 (s, 3H), 4.14(q, 2H), 4.35 (s, 2H), 6.79 (d, 2H), 6.91 (d, 2H), 7.10 (d, 2H), 7.60(d, 2H).

[0630] 6.9.2 N-4-Methoxyphenyl-N-4-Methoxybenzenesulfonyl-GlycineHydroxamic Acid

[0631] Freshly prepared hydroxylamine reagent (6 mL; 6 mmol) was addedto ethyl N-4-methoxyphenyl-N-4-methoxybenzenesulfonyl- glycinate (673mg; 1.77 mmol) and the resulting mixture stirred overnight at roomtemperature. The mixture was poured into 1 N HCl (40 mL) and extractedwith CH₂Cl₂ (2×40 mL). The combined extracts were washed with saturatedaqueous NaCl (40 mL), dried over MgSO₄, and evaporated under reducedpressure to give crude product. Trituration with diethyl ether afforded405 mg (63%) of the title compound as a white solid.

[0632]¹H-NMR (DMSO-d₆): δ3.72 (s, 3H), 3.84 (s, 3H), 4.06 (s, 2H), 6.84(d, 2H), 7.01 (d, 2H), 7.07 (d, 2H), 7.53 (d, 2H), 8.86 (bs, 1H), 10.57(s, 1H).

[0633] 6.10 SYNTHESIS OFN-(4-METHOXYPHENYL)ETHYL-N-4-METHOXYBENZENESULFONYL-GLYCINE HYDROXAMICACID (FG 204)

[0634] 6.10.1 Ethyl N-(4-Methoxyphenyl)Ethyl-N-4-MethoxybenzeneSulfonyl-Glycinate

[0635] N-(4-Methoxyphenyl) ethyl 4-methoxybenzenesulfonamide (1.50 g;4.67 mmol) was dissolved in dry DMF (20 mL) and stirred under argon.Sodium hydride, 60% in mineral oil (224 mg; 5.6 mmol), was added and theresulting mixture stirred at room temperature for 15 min. Ethylbromoacetate (780 mL; 7.00 mmol) was added and the reaction stirred atroom temperature for 2 h. The mixture was poured into diethyl ether (50mL) and the organic material washed with water, dried over Na₂SO₄,filtered, and evaporated to an oil. Preparative HPLC purification,eluting with a mixture of ethyl acetate/hexanes (35:65), gave 1.76 g(93%) of the title compound as a pale yellow oil.

[0636]¹H-NMR (CDCl₃): δ1.20 (t, 3H), 2.81 (t, 2H), 3.43 (t, 2H), 3.78(s, 3H), 3.85 (s, 3H), 3.98 (s, 2H), 4.08 (q, 2H), 6.81 (d, 2H), 6.94(d, 2H), 7.06 (d, 2H), 7.76 (d, 2H).

[0637] 6.10.2N-(4-Methoxyphenyl)Ethyl-N-4-Methoxybenzenesulfonyl-Glycine HydroxamicAcid

[0638] Freshly prepared hydroxylamine reagent (6 mL; 6 mmol) was addedto ethyl N-(4-methoxyphenyl)-ethyl-N-4-methoxybenzene sulfonyl-glycinate(758 mg; 1.86 mmol) and the resulting mixture stirred overnight at roomtemperature. The mixture was poured into 1 N HCl (40 mL) and extractedwith CH₂Cl₂ (2×40 mL). The combined extracts were washed with saturatedaqueous NaCl (40 mL), dried over MgSO₄, and evaporated under reducedpressure to give crude product. Trituration with diethyl ether afforded327 mg (44%) of the title compound as a white solid.

[0639]¹H-NMR (DMSO-d₆): δ2.69 (t, 2H), 3.25 (t, 2H), 3.71 (s, 3H), 3.73(s, 2H), 3.83 (s, 3H), 6.81 (d, 2H), 7.07 (m, 4H), 7.74 (d, 2H), 8.94(s, 1H), 10.63 (s, 1H).

[0640] 6.11 SYNTHESIS OFN-Hydroxy-3-[(4-methoxyphenethyl)-(4-methoxybenzenesulfonyl)-amino]-propionamide(FG 206)

[0641] 6.11.1 Ethyl3-[(4-methoxyphenethyl)-(4-methoxybenzenesulfonyl)-amino]-propionate

[0642] Ethyl acrylate (1.05 g; 10.0 mmol) and2-(4-methoxyphenyl)ethylamine (1.52 g; 10.0 mmol) were dissolved inabsolute ethanol (25 mL) and stirred overnight at room temperature. Thesolution was evaporated and crude ethyl3-(4-methoxyphenethy-amino]-propionate (1.25 g; 5.0 mmol) was dissolvedin CH₂Cl₂ (50 mL). 4-Methoxybenzenesulfonyl chloride (1.15 g; 5.5 mmol)and triethylamine (0.5 g; 5.0 mmol) were added and the mixture stirredovernight at room temperature. The reaction was washed with 1 N HCl(2×50 mL) and the aqueous layers back-extracted with CH₂Cl₂ (50 mL). Thecombined extracts were washed with saturated aqueous NaCl (100 mL),dried over MgSO₄, filtered, and evaporated to an oil. Preparative HPLCpurification, eluting with a mixture of ethyl acetate/hexanes (35:65),gave 1.86 g (88%) of the title compound as a pale yellow oil. 300 MHz¹H-NMR (CDCl₃): δ1.25 (t, 3H), 2.59 (t, 2H), 2.80 (m, 2H), 3.30 (m, 2H),3.42 (t, 2H), 3.78 (s, 3H), 3.86 (s, 3H), 4.11 (q, 2H), 6.82 (d, 2H),6.95 (d, 2H), 7.08 (d, 2H), 7.72 (d, 2H).

[0643] 6.11.2N-Hydroxy-3-[(4-methoxyphenethyl)-(4-methoxybenzenesulfonyl)-amino]-propionamide

[0644] Freshly prepared hydroxylamine reagent (6 mL; 6 mmol) was addedto ethyl3-[(4-methoxyphenethyl)-(4-methoxybenzenesulfonyl)-amino]-propionate(587 mg; 1.40 mmol) and the resulting mixture stirred overnight at roomtemperature. The mixture was poured into 1 N HCl (40 mL) and extractedwith CH₂Cl₂ (2×40 mL). The combined extracts were washed with saturatedaqueous NaCl (40 mL), dried over MgSO₄, and evaporated under reducedpressure to give crude product. Trituration with diethyl ether afforded408 mg (71%) of the title compound as a white solid. 300 MHz ¹H-NMR(DMSO-d₆): δ2.24 (t, 2H), 2.68 (t, 2H), 3.21 (t, 2H), 3.31 (m, 2H), 3.72(s, 3H), 3.84 (s, 3H), 6.84 (d, 2H), 7.11 (d, 4H), 7.71 (d, 2H), 8.78(s, 1H), 10.49 (s, 1H).

[0645] 6.12 SYNTHESIS OFN-Hydroxy-3-[(4-methoxyphenethyl)-(n-butanesulfonyl)-amino]-propionamide(FG 207)

[0646] 6.12.1 Ethyl3-[(4-methoxyphenethyl)-(n-butanesulfonyl)-amino]-propionate

[0647] Crude ethyl 3-(4-methoxyphenethyl-amino)-propionate (1.25 g; 5.0mmol) was dissolved in CH₂Cl₂ (50 mL). Butanesulfonyl chloride (1.57 g;10.0 mmol) and triethylamine (0.5 g; 5.0 mmol) were added and themixture stirred overnight at room temperature. The reaction was washedwith 1 N HCl (2×50 mL) and the aqueous layers back-extracted with CH₂Cl₂(50 mL). The combined extracts were washed with saturated aqueous NaCl(100 mL), dried over MgSO₄, filtered, and evaporated to an oil.Preparative HPLC purification, eluting with a mixture of ethylacetate/hexanes (35:65), gave 1.66 g (89%) of the title compound as apale yellow oil. 300 MHz ¹H-NMR (CDCl₃): δ0.90 (t, 3H), 1.26 (t, 3H),1.35 (m, 2H), 1.67 (m, 2H), 2.63 (t, 2H), 2.76 (m, 2H), 2.84 (t, 2H),3.42 (t, 2H), 3.54 (t, 2H), 3.78 (s, 3H), 4.15 (q, 2H), 6.84 (d, 2H),7.13 (d, 2H).

[0648] 6.12.2N-Hydroxy-3-[(4-methoxyphenethyl)-(n-butanesulfonyl)-amino]-propionamide

[0649] Freshly prepared hydroxylamine reagent (8 mL; 8 mmol) was addedto ethyl 3-[(4-methoxyphenethyl)-(n-butanesulfonyl)-amino]-propionate(935 mg; 2.52 mmol) and the resulting mixture stirred overnight at roomtemperature. The mixture was poured into 1 N HCl (40 mL) and extractedwith CH₂Cl₂ (2×40 mL). The combined extracts were washed with saturatedaqueous NaCl (40 mL), dried over MgSO₄, and evaporated under reducedpressure to give 545 mg (60%) as a gum which did not crystallize upontrituration with diethyl ether and hexanes. 300 MHz ¹H-NMR (DMSO-d₆):δ0.86 (t, 3H), 1.31, 2H), 1.54 (m, 2H), 2.28 (t, 2H), 2.76 (t, 2H), 2.96(m, 2H), 3.32 (t, 2H), 3.42 (t, 2H), 3.72 (s, 3H), 6.86 (d, 2H), 7.16(d, 2H), 8.79 (s, 1H), 10.52 (s, 1H).

[0650] 6.13 SYNTHESIS OFN-Hydroxy-3-[(4-methoxyphenyl)-(4-methoxybenzenesulfonyl)-amino]-propionamide(FG 208)

[0651] 6.13.1 Ethyl3-[(4-methoxyphenyl)-(4-methoxybenzenesulfonyl)-amino]-propionate

[0652] Ethyl acrylate (2.05 g; 20 mmol) and anisidine (2.46 g; 20 mmol)were added to a solution of concentrated HCl (1.5 mL) in absoluteethanol (20 mL) and the resulting mixture refluxed 48 h. The reactionwas cooled to room temperature and then poured into 1 N NaOH (100 mL)and extracted with ethyl acetate (2×100 mL). The combined organic layerswere washed with water (2×100 mL), dried over MgSO₄, filtered, andevaporated to give 3.15 g (70%) of a brown oil. A portion of the crudeethyl 3-(4-methoxyphenyl-amino)propionate (1.12 g; 5.0 mmol) wasdissolved in CH₂Cl₂ (50 mL). 4-Methoxybenzenesulfonyl chloride (1.15 g;5.5 mmol) and triethylamine (0.5 g; 5.0 mmol) were added and the mixturestirred overnight at room temperature. The reaction was washed with 1 NHCl (2×50 mL) and the aqueous layers back-extracted with CH₂Cl₂ (50 mL).The combined extracts were washed with saturated aqueous NaCl (100 mL),dried over MgSO₄, filtered, and evaporated to an oil. Preparative HPLCpurification, eluting with a mixture of ethyl acetate/hexanes (35:65),gave 1.42 g (72%) of the title compound as a pale brown oil. 300 MHz¹H-NMR (CDCl₃): δ1.20 (t, 3H), 2.52 (t, 2H), 3.78 (t, 2H), 3.79 (s, 3H),3.86 (s, 3H), 4.05 (q, 2H), 6.80 (m, 2H), 6.92 (m, 4H), 7.53 (m, 2H).

[0653] 6.13.2N-Hydroxy-3-[(4-methoxyphenyl)-(4-methoxybenzenesulfonyl)-amino]-propionamide

[0654] Freshly prepared hydroxylamine reagent (6 mL; 6 mmol) was addedto ethyl3-[(4-methoxyphenyl)-(4-methoxybenzene-sulfonyl)-amino]-propionate (507mg; 1.29 mmol) and the resulting mixture stirred overnight at roomtemperature. The mixture was poured into 1 N HCl (40 mL) and extractedwith CH₂Cl₂ (2×40 mL). The combined extracts were washed with saturatedaqueous NaCl (40 mL), dried over MgSO₄, and evaporated under reducedpressure to give 362 mg (74%) as a gum which did not crystallize upontrituration with diethyl ether and hexanes. 300 MHz ¹H-NMR (DMSO-d₆):δ2.24 (t, 2H), 3.67 (t, 2H), 3.75 (s, 3H), 3.84 (s, 3H), 6.90 (m, 4H),7.09 (d, 2H), 7.47 (d, 2H), 8.73 (s, 1H), 10.35 (s, 1H).

[0655] 6.14 SYNTHESIS OFN-Hydroxy-3-[(diphenylmethyl)-(4-methoxybenzenesulfonyl)-amino]-propionamide(FG 256)

[0656] 6.14.1 Ethyl3-[(diphenylmethyl)-(4-methoxybenzenesulfonyl)-amino]-propionate

[0657] Ethyl acrylate (1.05 g; 10.0 mmol) and diphenylmethyamine (1.83g; 10.0 mmol) were dissolved in absolute ethanol (25 mL) and stirredovernight at 70° C. The solution was evaporated and crude ethyl3-(diphenylmethylamino)propionate (2.85 g; 10.0 mmol) was dissolved inDMF (50 mL). 4-Methoxybenzenesulfonyl chloride (2.30 g; 11.0 mmol) andpyridine (10 mL) were added and the mixture stirred overnight at 70° C.The dark reaction was washed with 1 N HCl (2×100 mL). The combinedextracts were washed with saturated aqueous NaCl (100 mL), dried overMgSO₄, filtered, and evaporated to an oil. The black residue was elutedthrough a filter pad of silica gel using a hexanes/ethyl acetate stepgradient to remove polar material. Preparative HPLC purification,eluting with a mixture of ethyl acetate/hexanes (35:65), gave 1.06 g(23%) of the title compound as a pale yellow oil. 300 MHz ¹H-NMR(CDCl₃): δ1.16 (t, 3H), 2.12 (m, 2H), 3.57 (m, 2H), 3.84 (s, 3H), 3.99(q, 2H), 6.48 (s, 1H), 6.83 (d, 2H), 7.04 (m, 4H), 7.24 (m, 6H), 7.64(d, 2H).

[0658] 6.14.2N-Hydroxy-3-[(diphenylmethyl)-(4-methoxybenzenesulfonyl)-amino]-propionamide

[0659] Freshly prepared hydroxylamine reagent (8 mL; 8 mmol) was addedto ethyl3-[(diphenylmethyl)-(4-methoxybenzene-sulfonyl)-amino]-propionate (563mg; 1.24 mmol) and the resulting mixture stirred overnight at roomtemperature. The mixture was poured into 1 N HCl (100 mL) and extractedwith CH₂Cl₂ (2×50 mL). The combined extracts were washed with saturatedaqueous NaCl (100 mL), dried over MgSO₄, and evaporated under reducedpressure to give crude product. Trituration with diethyl ether afforded262 mg (48%) of the title compound as a white solid. 300 MHz ¹H-NMR(DMSO-d₆): δ1.81 (m, 2H), 3.40(m, 2H), 3.84 (s, 3H), 6.31 (s, 1H), 7.02(m, 6H), 7.28 (m, 6H), 7.71 (d, 2H), 8.59 (s, 1H), 10.23 (s, 1H).

[0660] 6.15 SYNTHESIS OFN-Hydroxy-3-[(4-chlorobenzyl)-(4-methoxybenzenesulfonyl)-amino]-propionamide(FG 1237)

[0661] 6.15.1 Ethyl3-[(4-chlorobenzyl)-(4-methoxybenzenesulfonyl)-amino]-propionate

[0662] To a solution of β-alanine ethyl ester (154 mg, 1 mmol) inanhydrous methylene chloride (7 mL) at room temperature was addedtriethyl amine (101 mg, 1 mmol) and 4-chlorobenzaldehyde (155 mg, 1.1mmol). After being stirred for 0.5 h, sodium triacetoxyborohydride (318mg, 1.5 mmol) was added and the reaction mixture was stirred foradditional 1 h at room temperature, followed by the addition of4-methoxybenzenesulfonyl chloride (207 mg, 1 mmol) and triethyl amine(152 mg, 1.5 mmol). The resulting mixture was stirred for 18 h, quenchedwith 10% citric acid (10 mL) and, after 30 min, extracted with methylenechloride (2×30 mL). Two phases was separated and the organic layers waswashed with brine, dried over MgSO₄, filtered, and concentrated. Thecrude product was purified by silica gel chromatography(2/1:hexanes/ethyl acetate) to give ethyl3-[(4-chlorobenzyl)-(4-methoxybenzenesulfonyl)-amino]-propionate (44 mg,0.1 mmol).

[0663] 6.15.2N-Hydroxy-3-[(4-chlorobenzyl)-(4-methoxybenzenesulfonyl)-amino]-propionamide(FG 1237)

[0664] Freshly prepared NH₂OH solution (1 M in methanol) (0.2 mL, 0.2mmol) was added to ethyl3-[(4-chlorobenzyl)-(4-methoxybenzenesulfonyl)-amino]-propionate (44 mg,0.1 mmol). After being stirred at room temperature for 18 h, thereaction mixture was concentrated. The crude product was triturated inether and the residue was lyophilized from water to giveN-hydroxy-3-[(4-chlorobenzyl)-(4-methoxybenzenesulfonyl)-amino]-propionamide(30 mg, 0.08 mmol) as a light yellow solid. ¹H-NMR (360 MHz, DMSO-d₆)δ7.75 (d, J=8.8 Hz, 2 H), 7.39 (d, J=8.5 Hz, 2 H), 7.32 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.8 Hz, 2 H), 4.28 (s, 2 H), 3.85 (s, 3 H), 3.20 (br t,J=7.8 Hz, 2 H), 1.86 (t, J=8.1 Hz, 2 H).

[0665] 6.16 SYNTHESIS OFN-Hydroxy-3-[(4-methoxyphenethyl)-(3-aminobenzenesulfonyl)-amino]-propionamide(FG 1492)

[0666] 6.16.1 Methyl3-[(4-Methoxyphenethyl)-(3-nitrobenzenesulfonyl)-amino]-propionate

[0667] A mixture of methyl acrylate (6.0 g, 69.7 mmol) andp-methoxyphenethyl amine (10.5 g, 69.7 mmol) in anhydrous methanol (88mL) was refluxed for 3 days and then was concentrated to give methyl3-[(4-methoxyphenethyl)amino]-propionate (16.2 g). To a solution ofmethyl 3-[(4-methoxyphenethyl)amino]-propionate (3.0 g, 12.6 mmol) inanhydrous methylene chloride (35 mL) was added 3-nitrobenzenesulfonylchloride (2.8 g, 12.6 mmol), followed by triethylamine (2.6 g, 25.3mmol). After stirring for 18 h at room temperature, the mixture wasquenched with 1 N HCl solution (150 mL) and extracted with methylenechloride (100 mL). Combined organic layers was washed successively with1 N HCl solution (100 mL) and brine, dried over MgSO₄, filtered, andconcentrated. The crude product was purified by silica gel flashchromatography (2.5/1 to 2/1:hexanes/EtOAc) to provide methyl3-[(4-methoxyphenethyl)-(4-cyanobenzenesulfonyl)-amino]-propionate (3.28g, 7.8 mmol).

[0668] 6.16.2 Methyl3-[(4-Methoxyphenethyl)-(3-aminobenzenesulfonyl)-amino]-propionate

[0669] To a clear solution of methyl3-[(4-methoxyphenethyl)-(3-nitrobenzenesulfonyl)-amino]-propionate in5/1 methanol/ethyl acetate (30 mL) was added 10% Pd/C (300 mg) andammonium formate (1.79 g, 28.4 mmol). After being stirred at roomtemperature for 24 h, the catalyst was filtered off through a pad ofcelite and the filtrate was concentrated. The residue was partitionedbetween methylene chloride (100 mL) and water (100 mL). Aqueous layerwas extracted with another 100 mL of methylene chloride. Combinedorganic layer was washed with water (100 mL) and brine, dried overNa₂SO₄, filtered, and concentrated to give methyl3-[(4-methoxyphenethyl)-(3-aminobenzenesulfonyl)-amino]-propionate (2.8g, 7.1 mmol) as a yellow gummy product.

[0670] 6.16.3N-Hydroxy-3-[(4-methoxyphenethyl)-(3-aminobenzenesulfonyl)-amino]-propionamide(FG 1492)

[0671] Freshly prepared NH₂OH solution (1 M in MeOH) (0.6 mL, 0.6 mmol))was added to methyl3-[(4-methoxyphenethyl)-(3-aminobenzenesulfonyl)amino]propionate (110mg, 0.28 mmol). After stirring at room temperature for 18 h, thereaction mixture was concentrated and taken up with 10 mL of water. Themixture was acidified to pH 3-4 by 1 N HCl solution and extracted withethyl acetate (2×20 mL). Combined organic layers was washed with brine,dried over MgSO₄, filtered and concentrated. The crude product waspurified by silica gel chromatography (10/1 methylene chloride/methanol)to giveN-hydroxy-3-[(4-methoxyphenethyl)-(3-aminobenzene-sulfonyl)amino]-propionamide(33 mg, 0.08 mmol). NMR (360 MHz, DMSO-d6) δ10.44 (s, 1 H), 8.72 (br s,1 H), 7.23 - 6.25 (m, 8 H), 5.57 (br s, 2 H), 3.70 (s, 3 H), 3.33 (t, 2H), 3.24 (t, 2 H), 2.65 (t, 2 H), 2.24 (t, 2 H).

[0672] 6.17 SYNTHESIS OFN-Hydroxy-3-[(4-methoxyphenethyl)-(4-(tetrazol-5yl)benzenesulfonyl)-amino]-propionamide(FG 1496)

[0673] 6.17.1 Methyl3-[(4-Methoxyphenethyl)-(4-cyanobenzene-sulfonyl)-amino]-propionate

[0674] A mixture of methyl acrylate (6.0 g, 69.7 mmol) andp-methoxyphenethyl amine (10.5 g, 69.7 mmol) in anhydrous methanol (88mL) was refluxed for 3 days and then was concentrated to give methyl3-[(4-methoxyphenethyl)amino]-propionate (16.2 g).

[0675] To a solution of methyl 3-[(4-methoxyphenethyl)amino]-propionate(3.0 g, 12.6 mmol) in anhydrous methylene chloride (35 mL) was added4-cyanobenzenesulfonyl chloride (2.6 g, 12.6 mmol), followed bytriethylamine (2.6 g, 25.3 mmol). After stirring for 18 h at roomtemperature, the mixture was quenched with 1 N HCl solution (150 mL) andextracted with methylene chloride (2×100 mL). Combined organic layerswas washed successively with 1 N HCl solution (100 mL) and brine, driedover MgSO₄₁ filtered, and concentrated. The crude product was purifiedby silica gel flash chromatography (2/1:hexanes/EtOAc) to provide methyl3-[(4-methoxyphenethyl)-(4-cyanobenzenesulfonyl)-amino]-propionate (3.14g, 7.8 mmol).

[0676] 6.17.2 Methyl3-[(4-Methoxyphenethyl)-(4-(tetrazol-5yl)-benzenesulfonyl)-amino]-propionate

[0677] A suspension of methyl3-[(4-methoxyphenethyl)-(4-cyanobenzenesulfonyl)-amino]-propionate (220mg, 0.55 mmol), sodium azide (43 mg, 0.66 mmol), and triethylaminehydrochloride (91 mg, 0.66 mmol) in anhydrous ethylene glycol dimethylether (3 mL) was fluxed for 48 h. Reaction mixture was concentrated,resuspended in water (10 mL) and extracted with ethyl acetate (2×20 mL).The organic layer was washed with 0.5 N HCl solution and brine, driedover MgSO₄. After filtration, the filtrate was concentrated to givemethyl3-[(4-methoxyphenethyl)-(4-(tetrazol-5yl)benzenesulfonyl)-amino]-propionate(112 mg, 0.25 mmol).

[0678] 6.18 SYNTHESIS OFN-Hydroxy-3-[(4-methoxyphenethyl)-(4-(tetrazol-5yl)benzenesulfonyl)-amino]-propionamide(FG 1496)

[0679] Freshly prepared NH₂OH solution (1 M in MeOH) (1.5 mL) was addedto methyl3-[(4-methoxyphenethyl)-(4-(tetrazol-5yl)-benzenesulfonyl)-amino]-propionate(112 mg, 0.25 mmol). After stirring at room temperature for 18 h, thereaction mixture was partitioned between 1 N HCl solution (20 mL) andethyl acetate (30 mL). Two phases were separated and the aqueous layerwas extracted with another 30 mL of ethyl acetate. Combined organiclayers were washed with brine, dried over MgSO₄, filtered andconcentrated to giveN-hydroxy-3-[(4-methoxyphenethyl)-(4-(tetrazol-5yl)benzenesulfonyl)amino]-propionamide(52 mg, 0.12 mmol). NMR (360 MHz, DMSO-d6) δ10.46 (s, 1 H), 8.74 (br s,1 H), 8.22 (d, J=8.4 Hz, 2 H), 7.99 (d, J=8.7 Hz, 2 H), 7.10 (d, J=8.2Hz, 2 H), 6.81 (d, J=8.2 Hz, 2 H), 3.69 (s, 3 H), 3.42 (t, J=7.5 Hz, 2H), 3.31 (t, J=7.9 Hz, 2 H), 2.70 (t, J=7.6 Hz, 2 H), 2.25 (t, J=7.5 Hz,2 H).

[0680] 6.19 N-Hydroxy-N′,N′-disubstituted-propionamides

[0681] N-Hydroxy-N′,N′-disubstituted-propionamides in examples 6.24.1thru 6.24.37 were prepared according to general reaction schemes I, II,and III. More specifically, the following steps were executed:

[0682] Step 1: Methyl acrylate or ethyl acrylate is added to a solutionof a primary amine in ethanol (1.3 mL/mmol). The mixture is heated toreflux (ca. 90° C.) for 20 h and then concentrated.

[0683] Step 2: The residue of step 1 is dissolved in methylene chloride(2.8 mL/mmol), followed by the addition of sulfonyl chloride (1 eq.) andAmberlyst (A-21) weakly basic ion exchange resin (0.8 g/mmol). Themixture is vortexed overnight at room temperature (ca.18 h), monitoredby TLC by observing the disappearance of sulfonyl chloride. The reactionmixture is filtered and concentrated.

[0684] Step 3: To the residue of Step 2 is added 2 equivalents offreshly prepared neutralized NH₂OH (1 M in methanol). The mixture isvortexed overnight (monitored by TLC), concentrated, followed by work upprocedure and/or chromatographic purification to affordN-hydroxy-N′,N′-disubstituted-propionamides. Two work up procedures areset up depending upon the feature of the product.

[0685] Step 4:

[0686] Work up procedure A: (For hydroxamates 6.24.1-6.24.27): Theresidue of step 3 is treated with 1 N HCl solution and extracted withethyl acetate. The organic layer is dried over MgSO₄₁ filtered, andconcentrated. The residue is then triturated with ether to removeundesired products which are discarded. The solid is collected and driedin vacco.

[0687] Work up procedure B: (For hydrophilic hydroxamates 6.24.28 to5.24.33): The residue of step 3 is triturated with ethyl acetate twice.Ethyl acetate is decanted and discarded. The residue is treated withwater, neutralized by 1 N HCl solution to pH=7-8, and extracted with10/1 ethyl acetate/methanol. The combined organic layers is washed withbrine, dried over magnesium sulfate, filtered, and concentrated. Theresidue is triturated in ether, which is discarded, and dried in vaccoto furnish the product as a white solid.

[0688] In the case that solid product formed during work up process, thesolid is collected, washed with ethyl acetate and dried in vacco.

[0689] In the case that TLC indicates low purity of the desired product,purification will be conducted using silica gel chromatography and/orrecrystallization.

[0690] Preparation of neutralized NH₂OH solution (1 M) in methanol: Awarm and clear solution of hydroxylamine hydrochloride in methanol (2mM/mL) (it becomes clear upon heating) is added to another warm andclear solution of potassium hydroxide in methanol (3 mM/mL) (it alsobecomes clear upon heating). White precipitate of potassium chlorideforms immediately. The mixture is cooled in an ice bath for 30 min. andfiltered. The fresh filtrate (1 M) is used for the hydroxamationreaction.

[0691] Preparation of 4-(3-Substituted-ureido)benzenesulfonyl choride:To a solution of primary or secondary amine (0.5 mmol) in THF (1 mL) at0° C. was added 4-(chlorosulfonyl)phenyl isocyanate (0.5 mmol). Afterstirring at 0° C. for 2 h, the mixture was concentrated to afford4-(3-substituted-ureido)benzenesulfonyl chloride. This material was thenused in Step B as described above.

[0692] 6.19.1 SYNTHESIS OFN-Hydroxy-3-[(adamantan-2-yl)-(4-methoxybenzenesulfonyl)-amino]-propionamide(FG 1335)

[0693] NMR (360 MHz, DMSO-d6) δ10.46 (s, 1 H), 8.68 (s, 1 H), 7.70 (d,J=8.8 Hz, 2 H), 7.09 (d, J=9.0 Hz, 2 H), 3.83 (s, 3 H), 3.47 (m, 2 H),2.34 (m, 2 H), 2.15-1.40 (m, 16H).

[0694] 6.19.2 SYNTHESIS OFN-Hydroxy-3-[(morpholin-4-yl-ethyl)-(4-methoxybenzenesulfonyl)-amino]-propionamide(FG 1131)

[0695] NMR (360 MHz, DMSO-d6) δ10.43 (s, 1 H), 8.71 (s, 1 H), 7.73 (d,J=9.2 Hz, 2 H), 7.10 (d, J=9.2 Hz, 2 H), 3.83 (s, 3 H), 3.52 (t, J=4.7Hz, 4 H), 3.28 (m, 2 H), 3.16 (t, J=7.8 Hz, 2 H), 2.40-2.33 (m, 6 H),2.25 (t, J=7.7 Hz, 2 H),

[0696] 6.19.3 SYNTHESIS OFN-Hydroxy-3-[(pyridin-2-yl-ethyl)-(4-methoxybenzenesulfonyl)-amino]-propionamide(FG 1132)

[0697] NMR (360 MHz, DMSO-d6) δ10.45 (s, 1 H), 8.74 (s, 1 H), 8.46 (d,J=4.8 Hz, 1 H), 7.68 (m, 3 H), 7.22 (m, 2 H), 7.09 (d, J=8.9 Hz, 2 H),3.82 (s, 3 H), 3.41 (t, J=7.8 Hz, 2 H), 3.31 (t, J=7.6 Hz, 2 H), 2.91(t, J=7.7 Hz, 2 H), 2.22 (t, J=7.4 Hz, 2 H).

[0698] 6.19.4 SYNTHESIS OFN-Hydroxy-3-[(phenethyl)-(4-nitrobenzenesulfonyl)-amino]-propionamide(FG 1268)

[0699] NMR (360 MHz, DMSO-d6) δ10.45 (s, 1 H), 8.75 (s, 1 H), 8.35 (d,J=8.7 Hz, 1 H), 8.03 (d, J=8.8 Hz, 1 H), 7.26-7.18 (m, 5 H), 3.43 (t,J=7.2 Hz, 2 H), 3.36 (t, J=7.9 Hz, 2 H), 2.78 9t, J=7.9 Hz, 2 H), 2.23(t, J=7.2 Hz, 2 H).

[0700] 6.19.5 SYNTHESIS OFN-Hydroxy-3-[(phenethyl)-(thiophen-2yl-sulfonyl)-amino]-propionamide (FG1270)

[0701] NMR (360 MHz, DMSO-d6) δ10.46 (s, 1 H), 8.74 (s, 1 H), 7.97 (d,J=4.8 Hz, 1 H), 7.66 (d, J=3.7 Hz, 1 H), 7.30-7.20 (m, 6 H), 3.36 (t,J=7.4 Hz, 2 H), 3.29 (m, 2 H), 2.77 (t, J=7.8 Hz, 2 H), 2.26 (t, J=7.4Hz, 2 H).

[0702] 6.19.6 SYNTHESIS OFN-Hydroxy-3-[(4-methoxyphenethyl)-(4-methylsulfonyl-benzenesulfonyl)-amino]-propionamide(FG 1460)

[0703] NMR (360 MHz, DMSO-d6) δ8.09 (d, J=8.1 Hz, 2 H), 8.00 (d, J=8.5Hz, 2 H), 7.10 (d, J=8.3 Hz, 2 H), 6.81 (d, J=8.5 Hz, 2 H), 3.70 (s, 3H), 3.37 (t, J=7.4 Hz, 2 H), 3.29 (m, 2 H), 2.71 (t, J=7.9 Hz, 2 H),2.10 (t, J=7.5 Hz, 2 H).

[0704] 6.19.7 SYNTHESIS OF N-Hydroxy-3-[(3,4-methylenedioxybenzyl)-(4-methoxybenzenesulfonyl)-amino]-propionamide (FG 1273)

[0705] NMR (360 MHz, DMSO-d6) δ10.34 (s, 1 H), 8.65 (s, 1 H), 7.75 (d,J=8.7 Hz, 2 H), 7.11 (d, J=8.8 Hz, 2 H), 6.84 (d, J=7.8 Hz, 1 H), 6.76(s, s, 1 H), 6.75 (d, J=7.8 Hz, 1 H), 5.99 (s, 2 H), 4.17 (s, 2 H), 3.84(s, 3 H), 3.21 (m, 2 H), 2.04 (m, 2 H).

[0706] 6.19.8 SYNTHESIS OFN-Hydroxy-3[(4-chlorophenethyl)-(4-methoxybenzenesulfonyl)-amino]-propionamide(FG 1300)

[0707] NMR (360 MHz, DMSO-d6) δ10.43 (s, 1 H), 8.74 (s, 1 H), 7.69 (d,J=8.7 Hz, 2 H), 7.31 (d, J=8.7 Hz, 2 H), 7.20 (d, J=8.4 Hz, 2 H), 7.08(d, J=8.6 Hz, 2 H), 3.83 (s, 3 H), 3.25 (m, 4 H), 2.73 (t, J=7.6 Hz, 2H), 2.21 (t, J=7.3 Hz, 2 H).

[0708] 6.19.9 SYNTHESIS OFN-Hydroxy-3[(cyclohexylethyl)-(4-methoxy-benzenesulfonyl)-amino]-propionamide(FG 1306)

[0709] NMR (360 MHz, DMSO-d6) δ10.42 (s, 1 H), 8.69 (s, 1 H), 7.70 (d,J=8.9 Hz, 2 H), 7.10 (d, J=8.7 Hz, 2 H), 3.83 (s, 3 H), 3.20 (t, J=7.8Hz, 2 H), 2.82 (d, J=7.4 Hz, 2 H), 2.18 (t, J=7.8 Hz, 2 H), 1.62 (m, 6H), 1.15 (m, 3 H), 0.82 (m, 2 H).

[0710] 6.19.10 SYNTHESIS OFN-Hydroxy-3-[benzodioxan-2-yl-methyl)-(4-methoxybenzene)-sulfonyl)-amino]-propionamide(FG 1374)

[0711] NMR (360 MHz, DMSO-d6) δ10.42 (s, 1 H), 8.70 (s, 1 H), 7.76 (d,J=8.7 Hz, 2 H), 7.11 (d, J=9.2 Hz, 2 H), 6.81 (m, 4 H), 4.36-4.27 (m, 2H), 3.96 (m, 1 H), 3.84 (s, 3 H), 3.37 (m, 4 H), 2.52 (m, 1 H), 2.30 (m,1 H).

[0712] 6.19.11 SYNTHESIS OFN-Hydroxy-3-[(3,4-methylenedioxybenzyl)-(thiophene-2-sulfonyl)-amino]-propionamide(FG 1371)

[0713] NMR (360 MHz, DMSO-d6) δ10.37 (s, 1 H), 8.68 (s, 1 H), 8.00 (d,J=4.8 Hz, 1 H), 7.69 (d, J=3.7 Hz, 1 H), 7.23 (dd, J=4.8, 3.9 Hz, 1 H),6.87-6.76 (m, 3 H), 6.00 (s, 2 H), 4.26 (s, 2 H), 3.28 (m, 2 H), 2.09(t, J=8.0 Hz, 2 H).

[0714] 6.19.12 SYNTHESIS OFN-Hydroxy-3-[(3,4-methylenedioxybenzyl)-(5-benzenesulfonylthiophene-2-sulfonyl)-amino]-propionamide(FG 1361)

[0715] NMR (360 MHz, DMSO-d6) δ10.39 (s, 1 H), 8.70 (s, 1 H), 8.06-7.66(m, 7 H), 6.79-6.70 (m, 3 H), 5.99 (s, 2 H), 4.29 (s, 2 H), 3.36 (t,J=7.7 Hz, 2 H), 2.11 (t, J=7.6 Hz, 2 H).

[0716] 6.19.13 SYNTHESIS OFN-Hydroxy-3[(3,4-methylenedioxybenzyl)-(4-n-butoxybenzenesulfonyl)-amino]-propionamide(FG 1372)

[0717] NMR (360 MHz, DMSO-d6) δ10.33 (s, 1 H), 8.64 (s, 1 H), 7.73 (d,J=8.5 Hz, 2 H), 7.10 (d, J=8.7 Hz, 2 H)m 6.85-6.74 (m, 3 H), 5.99 (s, 2H), 3.24 (m, 2 H), 2.04 (t, J=7.6 Hz, 2 H), 1.94 (m, 2 H), 1.76 (m, 2H), 1.44 (m, 2 H), 0.93 (t, J=7.4 Hz, 3 H).

[0718] 6.19.14 SYNTHESIS OFN-Hydroxy-3-[(3,4-methylenedioxybenzyl)-(octanesulfonyl)-amino]-propionamide(FG 1359)

[0719] NMR (360 MHz, DMSO-d6) δ10.43 (s, 1 H), 8.70 (s, 1 H), 6.96-6.80(m, 3 H), 6.00 (s, 2 H), 4.25 (s, 2 H), 3.27 (m, 2 H), 3.06 (t, J=7.9Hz, 2 H), 2.16 (t, J=7.5 Hz, 2 H), 1.62 (m, 2 H), 1.34-1.25 (m, 10 H),0.85 (t, J=6.9 Hz).

[0720] 6.19.15 SYNTHESIS OFN-Hydroxy-3-[(3,4-methylenedioxybenzyl)-(5-bromothiophene-2-sulfonyl)-amino]-propionamide(FG 1367)

[0721] NMR (360 MHz, DMSO-d6) δ10.38 (s, 1 H), 8.68 (s, 1 H), 7.54 (d,J=3.9 Hz, 1 H), 7.40 (d, J=3.6 Hz, 1 H), 6.80 (m, 3 H), 6.00 (s, 2 H),4.24 (s, 2 H), 3.31 (t, J=7.6 Hz, 2 H), 2.10 (t, J=7.8 Hz, 2 H).

[0722] 6.19.16 SYNTHESIS OFN-Hydroxy-3-[(3,4-methylenedioxybenzyl)-(4-acetylaminobenzenesulfonyl)-amino]-propionamide(FG 1357)

[0723] NMR (360 MHz, DMSO-d6) δ10.34 (s, 1 H), 7.78 (d, J=8.7 Hz, 2 H),7.74 (d, J=8.6 Hz, 2 H), 6.85-6.78 (m, 3 H), 5.99 (s, 2 H), 4.19 (s, 2H), 3.23 (m, 2 H), 2.08 (s, 3 H), 2.07 (m, 2 H).

[0724] 6.19.17 SYNTHESIS OFN-Hydroxy-3-[(3,4-methylenedioxybenzyl)-(3,4-dimethoxybenzene-sulfonyl)-amino]-propionamide(FG 1410)

[0725] NMR (360 MHz, DMSO-d6) δ7.39 (dd, J=8.4, 2.2 Hz, 1 H), 7.23 (d,J=2.3 Hz, 1 H), 7.12 (d, J 8.3 Hz, 1 H), 6.84 (m, 3 H), 5.99 (s, 2 H),4.21 (s, 2 H), 3.84 (s, 3 H), 3.82 (s, 3 H), 3.21 (t, J=8.0 Hz, 2 H),1.90 (t, J=8.1 Hz, 2 H).

[0726] 6.19.18 SYNTHESIS OFN-Hydroxy-3-[(3,4-methylenedioxybenzyl)-(benzo-2,1,3-thiadiazole-4-sulfonyl)-amino]-propionamide(FG 1362)

[0727] NMR (360 MHz, DMSO-d6) δ10.27 (s, 1 H), 8.58 (s, 1 H), 8.38 (d,J=8.7 Hz, 1 H), 8.22 (d, J=7.0 Hz, 1 H), 7.84 (dd, J=8.6, 7.2 Hz, 1 H),6.77-6.67 (m, 3 H), 5.96 (s, 2 H), 4.48 (s, 2 H), 3.52 (t, J=7.8 Hz, 2H), 2.02 (t, J=7.5 Hz, 2 H).

[0728] 6.19.19 SYNTHESIS OFN-Hydroxy-3-[(3,4-methylenedioxybenzyl)-(4-methylsulfonylbenzenesulfonyl)-amino]-propionamide(FG 1464)

[0729] NMR (360 MHz, DMSO-d6) δ8.12 (d, J=8.4 Hz, 2 H), 8.06 (d, J=8.7Hz, 2 H), 6.85-6.75 (m, 3 H), 5.99 (s, 2 H), 4.29 (s, 2 H), 3.29 (m, 2H), 2.49 (s, 3 H), 1.93 (t, J=7.7 Hz, 2 H).

[0730] 6.19.20 SYNTHESIS OFN-Hydroxy-3-[(2-thiophenethyl)-(phenylmethylsulfonyl)-amino]-propionamide(FG 1414)

[0731] NMR (360 MHz, DMSO-d6) δ10.46 (s, 1 H), 8.74 (s, 1 H), 7.38-7.31(m, 6 H), 6.94 (dd, J=5.1, 3.4 Hz, 1 H), 6.87 (d, J=3.4 Hz, 1 H), 4.37(s, 2 H), 3.33 (t, J=7.3 Hz, 2 H), 3.25 (m, 2 H), 2.94 (t, J=7.8 Hz, 2H), 2.23 (t, J=7.3 Hz, 2 H).

[0732] 6.19.21 SYNTHESIS OFN-Hydroxy-3-[(2-thiophenethyl)-(4-n-butoxybenzenesulfonyl)-amino]-propionamide(FG 1416)

[0733] NMR (360 MHz, DMSO-d6) δ10.43 (s, 1 H), 8.72 (s, 1 H), 7.69 (d,J=8.9 Hz, 2 H), 7.32 (d, J=5.2 Hz, 1 H), 7.09 (d, J=8.7 Hz, 2 H), 6.94(dd, J=5.2, 3.2 Hz, 1 H), 6.87 (d, J=2.4 Hz, 1 H), 4.05 (t, J=6.4 Hz, 2H), 3.28 (m, 2 H), 2.97 (t, J=7.5 Hz, 2 H), 2.22 (t, J=7.4 Hz, 2 H),1.70 (m, 2 H), 1.42 (m, 2 H), 0.92 (t, J=7.3 Hz, 3 H).

[0734] 6.19.22 SYNTHESIS OFN-Hydroxy-3-[(thiophen-2yl-ethyl)-(5-bromothiophen-2-sulfonyl)-amino]-propionamide(FG 1417)

[0735] NMR (360 MHz, DMSO-d6) δ10.46 (s, 1 H), 8.74 (s, 1 H), 7.53 (d,J=4.1 Hz, 1 H), 7.38 (d, J=4.1 Hz, 1 H), 7.34 (d, J=5.4 Hz, 1 H), 6.95(dd, J=5.0, 3.4 Hz, 1 H), 6.90 (d, J=3.0 Hz, 1 H), 3.37 (m, 4 H), 3.03(t, J=7.8 Hz, 2 H), 2.26 (t, J=7.4 Hz, 2 H).

[0736] 6.19.23 SYNTHESIS OFN-Hydroxy-3-[(2-thiophenethyl)-(2-thiophenesulfonyl)-amino]-propionamide(FG 1425)

[0737] NMR (360 MHz, DMSO-d6) δ10.46 (s, 1 H), 8.74 (s, 1 H), 7.98 (dd,J=4.8, 1.3 Hz, 1 H), 7.67 (dd, J=3.7, 1.3 Hz, 1 H), 7.34 (dd, J=5.1, 1.0Hz, 1 H), 7.23 (dd, J 5.0, 4.0 Hz, 1 H), 6.95 (dd, J=5.1, 3.2 Hz, 1 H),6.89 (d, J=2.3 Hz, 1 H), 3.35 (m, 4 H), 3.02 (t, J=7.7 Hz, 2 H), 2.26(t, J=7.3 Hz, 2 H).

[0738] 6.19.24 SYNTHESIS OFN-Hydroxy-3-[(2-thiophenethyl)-(5-benzenesulfonylthiophene-2-sulfonyl)-amino]-propionamide(FG 1419)

[0739] NMR (360 MHz, DMSO-d6) δ8.04 (d, J=7.5 Hz, 2 H), 7.89 (d, J=4.1Hz, 1 H), 7.76-7.65 (m, 4H), 7.28 (d, J=5.1 Hz, 1 H), 6.88 (dd, J=4.8,3.4 Hz, 1 H), 6.84 (d, J=3.1 Hz, 1 H), 3.37 (m, 4 H), 3.00 (t, J=7.6 Hz,2 H), 2.11 (t, J=7.4 Hz, 2 H).

[0740] 6.19.25 SYNTHESIS OFN-Hydroxy-3-[(2-thiophenethyl)-(4-acetylaminobenzenesulfonyl)-amino]-propionamide(FG 1411)

[0741] NMR (360 MHz, DMSO-d6) δ10.44 (s, 1 H), 10.31 (s, 1 H), 8.73 (s,1 H), 7.77 (d, J=8.8 Hz, 2 H), 7.71 (d, J=8.9 Hz, 2 H), 7.33 (d, J 5.1Hz, 1 H), 6.94 (dd, J=4.9, 3.4 Hz, 1 H), 6.88 (d, J=3.0 Hz, 1 H), 3.29(m, 4 H), 2.97 (t, J=7.7 Hz, 2 H), 2.21 (t, J=7.3 Hz, 2 H), 2.07 (s, 3H).

[0742] 6.19.26 SYNTHESIS OFN-Hydroxy-3-[(2-thiophenethyl)-(4-methylsulfonylbenzenesulfonyl)-amino]-propionamide(FG 1463)

[0743] NMR (360 MHz, DMSO-d6) δ8.11 (d, J=8.6 Hz, 2 H), 8.02 (d, J=8.6Hz, 2 H), 7.32 (d, J=5.1 Hz, 1 H), 6.94-6.88 (m, 2 H), 3.37 (m, 4 H),3.29 (t, J=7.4 Hz, 2 H), 2.10 (t, J=7.7 Hz, 2 H).

[0744] 6.19.27 SYNTHESIS OFN-Hydroxy-3-[(2-methoxy-phenethyl)-(4-carboxy-benzenesulfonyl)-amino]-propionamide(FG 1405)

[0745] NMR (360 MHz, DMSO-d6, room temp.) δ10.50 (s, 1 H), 8.75 (s, 1H), 7.79-6.72 (m, 8 H), 3.76 (s, 3 H), 3.66 (br t, J=6.8 Hz, 1 H), 3.38(m, 1 H), 3.25 (m, 2 H), 2.67 (m, 2 H), 2.34 (br t, J=6.8 Hz, 1 H), 2.28(br t, J=7.1 Hz, 1 H).

[0746] 6.19.28 SYNTHESIS OFN-Hydroxy-3-[(3,4-methylenedioxybenzyl)-(4-(N′-hydroxyamidino)benzenesulfonyl)-amino]-propionamide(FG 1369)

[0747] NMR (360 MHz, DMSO-d6) δ10.36 (s, 1 H), 9.94 (s, 1 H), 8.66 (s, 1H), 7.89 (d, J=8.2 Hz, 2 H), 7.81 (d, J=8.4 Hz, 2 H), 6.85 (d, J=7.8 Hz,1 H), 6.77 (m, 2 H), 5.99 (s, 2 H), 5.95 (s, 2 H), 4.23 (s, 2 H), 3,25(m, 2 H), 2.05 (t, J=7.7 Hz, 2 H).

[0748] 6.19.29 SYNTHESIS OFN-Hydroxy-3-[(3,4-methylenedioxybenzyl)-(3-(N′-hydroxyamidino)benzenesulfonyl)-amino]-propionamide(FG 1458)

[0749] NMR (360 MHz, DMSO-d6) δ10.36 (s, 1 H), 9.87 (s, 1 H), 8.97 (s, 1H), 8.11 (s, 1 H), 7.96 (d, J=8.1 Hz, 1 H), 7.81 (d, J=8.2 Hz, 1 H),7.62 (t, J=7.9 Hz, 1 H), 6.83 (m, 3 H), 6.00 (s, 2 H), 5.99 (s, 2 H),4.23 (s, 2 H), 3.27 (m, 2 H), 2.05 (m, 2 H).

[0750] 6.19.30 SYNTHESIS OFN-Hydroxy-3-[(4-methoxyphenethyl)-(4-(N′-hydroxyamidino)benzenesulfonyl)-amino]-propionamide(FG 1455)

[0751] NMR (360 MHz, DMSO-d6) δ10.46 (s, 1 H), 9.91 (s, 1 H), 8.74 (s, 1H), 7.86 (d, J=8.9 Hz, 2 H), 7.76 (d, J=9.0 Hz, 2 H), 7.09 (d, J=8.3 Hz,2 H), 6.82 (d, J=9.0 Hz, 2 H), 5.92 (s, 2 H), 3.70 (s, 3 H), 3.35 (t,J=7.6 Hz, 2 H), 3.25 (m, 2 H), 2.67 (t, J=8.1 Hz, 2 H), 2.24 (t, J=7.3Hz,2 H).

[0752] 6.19.31 SYNTHESIS OFN-Hydroxy-3-[(4-methoxyphenethyl)-(3-(N′-hydroxyamidino)benzenesulfonyl)-amino]-propionamide(FG 1456)

[0753] NMR (360 MHz, DMSO-d6) δ10.47 (s, 1 H), 9.86 (s, 1 H), 8.75 (s, 1H), 8.08 (s, 1H), 7.94 (d, J=7.7 Hz, 1 H), 7.76 (d, J=7.9 Hz, 1 H), 7.60(t, J=8.1 Hz, 1 H), 7.08 (d, J=8.1 Hz, 2 H), 6.82 (d, J=8.4 Hz, 2 H),5.99 (s, 2 H), 3.36 (m, 2 H), 3.25 (m, 2 H), 2.66 (t, J=7.7 Hz, 2 H),2.24 (t, J=7.4 Hz, 2 H).

[0754] 6.19.32N-Hydroxy-3-[(2-thiophenethyl)-(3-(N′-hydroxyamidino)benzenesulfonyl)-amino]-propionamide(FG 1457)

[0755] NMR (360 MHz, DMSO-d6) δ10.46 (s, 1 H), 9.86 (s, 1 H), 8.74 (s, 1H), 8.08 (s, 1 H), 7.95 (d, J=7.6 Hz, 1 H), 7.77 (d, J=8.6 Hz, 1 H),7.61 (t, J=7.8 Hz, 1 H), 7.31 (dd, J=5.3 Hz, 1 H), 6.87 (m, 2 H), 6.00(s, 2 H), 3.35 (m, 4 H), 2.98 (t, J=7.7 Hz, 2 H), 2.23 (t, J=7.6 Hz, 2H).

[0756] 6.19.33 SYNTHESIS OFN-Hydroxy-3-[(2-thiophenethyl)-(4-(N′-hydroxyamidino)-benzenesulfonyl)-amino]-propionamide(FG 1409)

[0757] NMR (360 MHz, DMSO-d6) δ10.45 (s, 1 H), 9.92 (s, 1 H), 8.74 (s, 1H), 7.87 (d, J=8.7 Hz, 2 H), 7.77 (d, J=8.4 Hz, 2 H), 7.32 (d, J=5.1 Hz,1 H), 6.94 (dd, J=5.1, 3.5 Hz, 1 H), 6.88 (d, J=3.4 Hz, 1 H), 5.93 (s, 2H), 3.35 (m, 4 H), 2.99 (t, J=7.8 Hz, 2 H), 2.23 (t, J=7.3 Hz, 2 H).

[0758] 6.20 SYNTHESIS OFN-Hydroxy-3-[(4-methoxyphenethyl)-(4-(3-(4-chlorophenyl)ureido)benzenesulfonyl)-amino]-propionamide(FG 1730)

[0759] Compound 1730 can be made using reaction scheme 10. NMR (360 MHz,DMSO-d6) δ10.46 (s, 1 H), 9.16 (s, 1 H), 8.91 (s, 1 H), 8.74 (s, 1 H),7.68 (d, J=9.2 Hz, 2 H), 7.62 (d, J=8.7 Hz, 2 H), 7.47 (d, J=8.6 Hz, 2H), 7.32 (d, J=9.2 Hz, 2 H), 7.10 (d, J=8.7 Hz, 2 H), 6.83 (d, J=8.7 Hz,2 H), 3.71 (s, 3 H), 3.22 (t, J=7.2 Hz, 2 H), 3.21 (t, J=8.0 Hz, 2 H),2.67 (t, J=7.9 Hz, 2 H), 2.23 (t, J=7. 2 Hz, 2 H).

[0760] 6.21 SYNTHESIS OFN-Hydroxy-3-[(4-methoxyphenethyl)-(4-(3-benzyl-ureido)benzenesulfonyl)-amino]-propionamide(FG 1731)

[0761] Compound 1731 can be made using reaction scheme 10. NMR (360 MHz,DMSO-d6) δ10.45 (s, 1 H), 9.04 (s, 1 H), 8.98 (s, 1 H), 8.73 (s, 1 H),7.87-6.82 (m, 13 H), 4.30 (d, J=5.8 Hz, 2 H), 3.70 (s, 3 H), 3.30 (m, 2H), 3.19 (t, J=7.5 Hz, 2 H), 2.66 (t, J=7.7 Hz, 2 H), 2.21 (t, J=7.3 Hz,2 H).

[0762] 6.22 SYNTHESIS OFN-Hydroxy-3-[(4-methoxyphenethyl)-(4-(3-phenethyl-ureido)benzenesulfonyl)-amino]-propionamide(FG 1732)

[0763] Compound 1732 can be made using reaction scheme 10. NMR (360 MHz,DMSO-d6) δ10.44 (s, 1 H), 8.95 (s, 1 H), 8.89 (s, 1 H), 8.72 (s, 1 H),7.62-6.81 (m, 13 H),3.71 (s, 3 H), 3.34 (m, 4 H), 3.19 (t, J=7.9 Hz, 2H), 2.75 (t, J=7.2 Hz, 2 H), 2.65 (t, J=7.0 Hz, 2 H), 2.21 (t, J=7.4 Hz,2 H).

[0764] 6.23 SYNTHESIS OFN-Hydroxy-3-[(4-methoxyphenethyl)-(4-(3-methyl-ureido)benzenesulfonyl)-amino]-propionamide(FG 1733)

[0765] Compound 1733 can be made using reaction scheme 10. NMR (360 MHz,DMSO-d6) δ10.45 (s, 1 H), 8.98 (s, 1 H), 8.73 (s, 1 H), 7.59 (m, 4 H),7.09 (d, J=8.9 Hz, 2 H), 6.83 (d, J=8.8 Hz, 2 H), 3.70 (s, 3 H), 3.30(m, 2 H), 3.18 (t, J=8.0 Hz, 2 H), 2.67 (m, 2 H), 2.64 (d, J=4.5 Hz, 3H), 2.21 (t, J=7.3 Hz, 2 H).

[0766] 6.24 SYNTHESIS OF FG 2032

[0767] To a clear solution of methyl3-[(4-methoxyphenethyl)-(4-nitrobenzensulfonyl)-amino]-propionate in 5:1methanol/ethyl acetate (4.2 mL/mmol) is added by portion palladium (10%)in charcoal solid (10% w/w), followed by ammonium formate (4 eq.). Theresulting mixture is refluxed for 6 hours and filtered through a pad ofcelite. Filtrate is concentrated and partitioned between ethyl acetateand water. The organic layer is washed with brine, dried over sodiumsulfate, filtered and concentrated to give methyl3-[(4-methoxyphenethyl)-(4-aminobenzenesulfonyl)-amino]-propionate as abrown oily product in quantitative yield.

[0768] To a solution of methyl3-[(4-methoxyphenethyl)-(4-aminobenzenesulfonyl)-amino]-propionate inacetonitrile (7.8 mL/mmol) is added benzoyl chloride followed bytriethyl amine (2 eq.). The mixture is stirred at room temperature for 5hours and then partitioned between methylene chloride and 0.1 Nhydrochloric acid aqueous solution. The acid layer is extracted withmethylene chloride. Combined organic layers are washed with brine, driedover magnesium sulfate, filtered, and concentrated. The residue is thentreated with 10 equivalents of freshly prepared neutralized NH₂OH (1 Min methanol). The mixture is stirred at room temperature for 5 hours andconcentrated. The residue is partitioned between 10:1 ethylacetate/methanol and 1 N hydrochloric acid aqueous solution. The organiclayer is washed with brine, dried over magnesium sulfate, filtered, andconcentrated to give the corresponding hydroxamic acid FG 2032.

[0769] 6.25 SYNTHESIS OF FG 2033

[0770] To a clear solution of methyl3-[(4-methoxyphenethyl)-(4-nitrobenzensulfonyl)-amino]-propionate in 5:1methanol/ethyl acetate (4.2 mL/mmol) is added by portion palladium (10%)in charcoal solid (10% w/w), followed by ammonium formate (4 eq.). Theresulting mixture is refluxed for 6 hours and filtered through a pad ofcelite. Filtrate is concentrated and partitioned between ethyl acetateand water. The organic layer is washed with brine, dried over sodiumsulfate, filtered and concentrated to give methyl3-[(4-methoxyphenethyl)-(4-aminobenzenesulfonyl)-amino]-propionate as abrown oily product in quantitative yield.

[0771] To a solution of methyl3-[(4-methoxyphenethyl)-(4-aminobenzenesulfonyl)-amino]-propionate inacetonitrile (7.8 mL/mmol) is added benzenesulfonyl chloride followed bytriethyl amine (2 eq.). The mixture is stirred at room temperature for 5hours and then partitioned between methylene chloride and 0.1 Nhydrochloric acid aqueous solution. The acid layer is extracted withmethylene chloride. Combined organic layers are washed with brine, driedover magnesium sulfate, filtered, and concentrated. The residue is thentreated with 10 equivalents of freshly prepared neutralized NH₂OH (1 Min methanol). The mixture is stirred at room temperature for 5 hours andconcentrated. The residue is partitioned between 10:1 ethylacetate/methanol and 1 N hydrochloric acid aqueous solution. The organiclayer is washed with brine, dried over magnesium sulfate, filtered, andconcentrated to give the corresponding hydroxamic acid FG 2033.

[0772]6.26 Synthesis of Other Compounds

[0773] Other compounds of the invention can be synthesized by routinemodification of the above-described syntheses, or by other methods thatare well-known in the art. Appropriate starting materials arecommercially available or can by synthesized using routine methods.

7. EXAMPLE C-proteinase IC₅₀ Assays

[0774] The following assay may be used to determine the level ofactivity and effect of the different compounds of the present inventionon C-proteinase activity.

[0775] To determine inhibition of recombinant human C-proteinase, 60 μlof a reaction mix (final concentration in 100 μl of 0.05M Tris-HCl pH7.6, 0.1M NaCl, 0.02% Brij-35, 5 mM CaCl₂, and 50 μM of a fluorogenicpeptide) was added to 20 μl of the inhibitor in a 96 well plate. Thereaction was started with the addition of 20 μl of the recombinant humanC-proteinase mix. The reaction proceeded for 4 hours at 37° C. and thefluorescence was measured using a Bio-Tek Fl-600. The IC₅₀ wasdetermined by plotting the percentage of activity versus the inhibitorconcentration and estimating the inhibitor concentration that gives 50%activity of the control with no inhibitor.

[0776] The IC₅₀ value of the inhibitors that have been tested is shownin TABLE 1. TABLE 1 IC₅₀ (μM) Of Various C-Proteinase InhibitorsCompound (FG#) IC₅₀ (μM) 121 9 122 10 123 39 124 2 125 29 126 1 128 15.3134 7 202 72.8 204 22.1 206 1.05 208 1.68 1131 80.5 1132 8 1268 3.031237 3.57 1270 1.21 1273 0.63 1300 2.43 1301 14.5 1302 5.7 1306 1.711335 36.5 1357 0.55 1360 1.17 1361 0.88 1362 1.51 1363 12.38 1364 2.601365 0.59 1366 2.85 1367 1.47 1368 6.01 1369 0.23 1370 0.87 1371 0.911372 1.70 1373 0.35 1379 >10 1380 >10 1405 1.46 1407 0.58 1408 0.75 14090.18 1410 1.77 1411 0.39 1414 3.50 1415 3.85 1416 0.82 1417 1.67 14185.37 1419 3.95 1420 3.00 1421 13.7 1422 8.36 1423 2.61 1424 8.88 14251.32 1455 0.086 1456 0.4 1457 0.84 1458 0.25 1459 7.12 1460 0.29 146112.90 1462 19.13 1463 0.70 1464 0.35 1465 9.07 1466 17.49 1467 8.39 14682.42 1469 15.39 1470 9.07 1471 4.08 1472 6.32 1473 8.85 1492 0.32 14960.25 1730 0.3 1731 0.010 1732 0.045 1733 0.057 1858 0.01 1891 0.026 18940.01 1895 0.784 1896 0.141 1943 0.81 1944 0.092 2032 0.41 2033 0.47

[0777] 7.1 Tissue Culture Assay for the Determination of C-proteinaseActivity and the IC₅₀ of Inhibitors

[0778] C-proteinase activity and the IC₅₀ of inhibitors in vivo may bedetermined in tissue culture assays by measuring the production ofprocollagen and mature collagen in conditioned medium before and aftertreatment with a particular compound. The ratio of collagen andprocollagen will directly correlate to the cellular conversion of theprecursor to the mature collagen product, and as such indicate theC-proteinase activity.

[0779] Alternatively, the media content of C-propeptide/cell may bedetermined, and compared for untreated cells and inhibitor-treatedcells.

[0780] 7.2 Animal Models for the Determination of C-proteinase Activityand the Efficacy of Inhibitors

[0781] Several animal models which mimic clinical disorders related tounregulated or inappropriate collagen production are known in the artand may be employed to determine the in vivo efficacy of the compoundsof the invention. These animal models include a wound chamber model inrats (Schilling et al., 1959, Surgery 46:702-710), an estradiolstimulated uterus expansion model (Mandell et al., 1982, The Journal ofBiological Chemistry 257:5268-5273), and an induced angiogenesis model(Matrigel) (Passaniti et al., 1992, Laboratory Investigation67:519-528). Further animal models include clinical disorder models likeliver fibrosis models (Tsukamoto et al., 1990, Seminar in Liver Disease10:56-65; Kock-Weser, 1952, Laboratory Investigation 1:324-331;Marrione, 1949, American Journal of Pathology 25:273-285; Tams, 1957,American Journal of Pathology 33:13-27; Wahl et al., 1986, Journal ofExperimental Medicine 163:884-902), a pulmonary fibrosis model (Kelly etal., 1980, Journal of Laboratory Clinical Medicine 96:954-964), arterialrestenosis models (Jackson, 1994, Trends of Cardiovascular Medicine4:122-130; Clowes et al., 1983, Laboratory Investigation 49:327-333), akidney fibrosis model (Yamamoto et al., 1987, Kidney International32:514-525), a tendon repairing model (Franklin et al., 1986, TheJournal of Laboratory and Clinical Medicine 108:103-108), a tumor growthmodel (Kiohs, et al., 1985, JNCL 75:353-359), a trabeculectomy model(Lahery et al., 1989, Journal of Ocular Pharmacology 5:155-179), and anabdominal adhesions model (Williams et al., 1992, Journal of SurgicalResearch 52:65-70).

[0782] 7.3 Measurement of Cytotoxicity

[0783] C-proteinase inhibitors were studied in cytotoxicity assayswherein quiescent cells were exposed to C-proteinase inhibitors for agiven time and cell viability measured. By examining cellular metabolicactivity, cell viability and cell survival were determined.

[0784] C-proteinase inhibitors were tested on human foreskin fibroblaststhat had been grown to confluence in 96 well microtiter plates inDulbecco's Modified Eagle Medium (DMEM) containing 10% fetal calf serum.Shortly before adding the inhibitors, the media was removed and 90 μlper microtiter well of fresh serum-free DMEM was added to the cells. TheC-proteinase inhibitors were made up as concentrated stocks containingcompound at 250 μM in the presence of 5% DMSO as solvent. A concentratedstock of 10 μl was added to each microtiter well to give a finalcompound concentration of 25μM in the presence of 0.5% DMSO. The cellswere incubated in the presence of the C-proteinase inhibitor for 48hours, and then cell viability and survival were measured as a functionof metabolic activity. To examine cellular metabolic activity, 10 μl ofWST-1 reagent (Boehringer Mannheim) was added to each well of a 96 wellmicrotiter plate containing quiescent cells that were already in media.The plate was incubated at 37° C. for 120 minutes and removed. Theabsorbance at 450 nm-650 nm was recorded. Increased absorbance wasobserved in cells that were healthy. Controls included untreated healthycells, and cells killed with 0.1% saponin.

[0785] Cytotoxicity was evaluated as a function of cellular survival.Cellular survival was determined by measuring the metabolic activity ofthe quiescent cells after exposure to the C-proteinase inhibitors. Todetermine the metabolic activity of the cells, the color change of atrazolium dye over time was examined according to Mossmann, 1938,Immunol. Methods 65:66; Carmichael, 1987, Cancer Res 47:936,incorporated herein by reference. Healthy cells cleaved the dyeproducing a colored product that can be quantitated. Unhealthy cellsdemonstrated a reduction in metabolic activity and reduced color change.Dead cells had no metabolic activity and no effect on the dye was shown.

[0786] The amount of dye cleaved by cells that had been incubated withinhibitor, expressed as a percentage relative to untreated cells, isshown in TABLE 2. Cells that register at 60% or below are consideredeither very sick or dead. Control cells that were intentionally killedgive a value of close to 20%. TABLE 2 Percent Metabolic Activity ofFibroblasts Exposed To Various C-Proteinase Inhibitors Relative toUntreated Fibroblasts Compound Percent 1300 109.9 1301 110.7 1302 102.31305 93.9 1306 106.3 1335 113.3 1357 108.1 1359 101.1 1360 114.5 1361103.4 1362 119.4 1363 114.9 1364 117.2 1365 121.2 1366 107.4 1367 114.51368 110.2 1369 117.1 1370 117.9 1371 114.4 1372 109.2 1373 103.2 1374117.6 1379 100.3 1380 107.7 1405 114.5 1407 111.5 1408 113.1 1409 108.81410 108.6 1411 108.2 1414 112.6 1415 109.6 1416 92.8 1417 120.3 1418101.0 1419 104.7 1420 124.4 1421 118.2 1422 118.6 1423 119.9 1424 111.71425 109.5 1455 115.1 1456 106.8 1457 107.4 1458 111.0 1459 107.3 1460108.9 1461 112.7 1462 112.6 1463 110.0 1464 111.0 1465 105.4

[0787] 7.5 Specificity

[0788] The compounds of the present invention were assayed against othermatrix metalloproteinases (MMPs) to determine compound specificity. MMP1(collagenase), MMP2 (gelatinase) and MMP9 (gelatinase B) were assayedaccording to the protocols provided in WO 93/34918 for MMP1 and MMP2.The specificity of selected compounds of the present invention againstMMP1, MMP2 and MMP9 are provided in Table 3. TABLE 3 IC50 (uM) of SelectC-Proteinase Inhibitors Against MMPs IC₅₀ of IC₅₀ of IC₅₀ of IC₅₀ ofMMP1/CPase MMP2/CPase MMP9/CPase FG # Cpase (μM) (μM) (μM) (μM) 1261.8 >8.0 2.2 3.5 206 1.05 >10.7 2.1 1.5 208 1.68 >11.2 0.46 0.30 14550.086 >3.6 >4.5 >4.5 1731 0.01 >891 >742.5 >742.5 17320.032 >255 >360.5 >360.5 1858 0.01 >1061 >855.0 >855.0 18910.026 >112.1 >112.1 1894 0.01 >516 94.9 >253.9

[0789] The present invention is not to be limited in scope by theexemplified embodiments which are intended as illustrations of singleaspects of the invention, and any compounds and methods for the usethereof which are functionally equivalent are within the scope of theinvention. Indeed, various modifications of the invention in addition tothose described herein will become apparent to those skilled in the artfrom the foregoing description and accompanying drawings. Suchmodifications are intended to fall within the scope of the appendedclaims.

[0790] All references cited herein are hereby incorporated by referencein their entirety.

What is claimed:
 1. A compound having an inhibitory effect onC-proteinase and having the structural formula:

or pharmaceutically acceptable salts thereof, wherein: a is an integerfrom 1 to 4; b is an integer from 0 to 4; c is an integer from 0 to 4;Ar¹ is selected from the group consisting of (C₅-C₂₀) aryl, (C₅-C₂₀)aryl independently substituted with one or more Y¹, 5-20 memberedheteroaryl, and 5-20 membered heteroaryl independently substituted withone or more Y¹; Ar² is selected from the group consisting of (C₅-C₂₀)aryl, (C₅-C₂₀) aryl independently substituted with one or more Y², 5-20membered heteroaryl, and 5-20 membered heteroaryl independentlysubstituted with one or more Y²; each Y¹ is independently selected fromthe group consisting of an electron-donating functional group, anelectron-withdrawing functional group, and a lipophilic functionalgroup; and each Y² is independently selected from the group consistingof a functional group having an acidic hydrogen, a functional groupcapable of participating in a hydrogen bond, a polar functional group,an electron-withdrawing functional group, an electron-donatingfunctional group, and a lipophilic functional group, with the provisosthat (i) when a and b are each one, c is zero and Ar² is4′-methoxyphenyl, then Ar¹ is other than phenyl, 4′-fluorophenyl,4′-chlorophenyl, 4′-trifluoromethylphenyl or 4′-methoxyphenyl; (ii) whena and b are each one, c is zero and Ar² is phenyl, then Ar¹ is otherthan 4′-chlorophenyl; (iii) when a is two, b and c are each zero and Ar¹is phenyl, then Ar² is other than 4′-chlorophenyl or 4′-bromophenyl; and(iv) when a and b are each one, c is zero and Ar² is phenyl, then Ar¹ isother than carbocyclic aryl-lower alkyl, carbocyclic aryl, heterocyclicaryl, biaryl, biaryl-lower alkyl, heterocyclic aryl-lower alkyl, or(N-aryl-lower alkylpiperazino)-lower alkyl, wherein, in proviso (iv),aryl represents monocyclic or bicyclic aryl, carbocyclic aryl representsmonocyclic or bicyclic carbocyclic aryl and heterocyclic aryl representsmonocyclic or bicyclic heterocyclic aryl.
 2. The compound of claim 1wherein Y¹ and Y² are each independently selected from the groupconsisting of halogen, —R, —OR, —SR, —NRR, —NO, —NO₂, —CN,-trihalomethyl, and —SO₂NH₂; where each R is independently selected fromthe group consisting of H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl, and (C₂-C₈)alkynyl.
 3. The compound of claim 1 wherein each Y² is independentlyselected from the group consisting of -halogen, -trihalomethyl, —R,—C(O)OR, —CN, —C(O)—NR—OR, —C(NRR)═N—OR, —C(O)—R, —C(O)NRR, —C(S)NRR,—C(NHR)═NR, —NRR, —NO₂, —NH—C(O)R, —NH—C(O)—NRR, —NH—C(O)—OR, —NH—SO₂—R,—NH—C(S)—NRR, ,—NH—C(O)R, —NR—C(O)—NRR, —NR—C(S)—NRR, —OR,—P(O)(OH)(NRR), —P(O)(OH)₂, —SO₂R, —S(O)—R, —SO₃H, —SR, and -tetrazole;where each R is independently selected from the group consisting ofH,(C₁-C₈) alkyl, (C₂-C₈) alkenyl, (C₂-C₈) alkynyl, (C₅-C₂₀) aryl,(C₆-C₂₅) alkaryl, 5-20 membered heteroaryl and 6-26 memberedalk-heteroaryl.
 4. The compound of claim 1 wherein Ar¹ is selected fromthe group consisting of (C₅-C₂₀) aryl and (C₅-C₂₀) aryl independentlysubstituted with one or more Y¹; and Ar² is selected from the groupconsisting of (C₅-C₂₀) aryl and (C₅-C₂₀) aryl independently substitutedwith one or more Y².
 5. The compound of claim 4 having the structuralformula:

or pharmaceutically acceptable salts thereof, wherein a, b, and c are asdefined in claim 1; R¹, R², R³, R⁴ and R⁵ are each independentlyselected from the group consisting of H, an electron-donating functionalgroup, an electron-withdrawing functional group, and a lipophilicfunctional group; R⁶, R⁷, R⁸, R⁹ and R¹⁰ are each independently selectedfrom the group consisting of H, a functional group having an acidichydrogen, a functional group capable of participating in a hydrogenbond, a polar functional group, an electron-withdrawing functionalgroup, an electron-donating functional group, and a lipophilicfunctional group; with the provisos that (i) when a and b are each onethen c is other than zero; and (ii) when a is two, b and c are each zeroand R¹, R², R⁴, R⁵, R⁶, R⁷, R⁹ and R¹⁰ are each —H, then R⁸ is otherthan —F or —Cl.
 6. The compound of claim 5 wherein R¹, R², R³, R⁴ and R⁵are each independently selected from the group consisting of —R,halogen, —OR, —SR, —NRR, —COOH, —SO₃H, —P(O)(OH)₂, —C(O)—NH—OH,—P(O)(OH)(NRR), and tetrazole; where each R is independently selectedfrom the group consisting of H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl and(C₂-C₈) alkynyl.
 7. The compound of claim 5 wherein R⁶, R⁷, R⁸, R⁹ andR¹⁰) are each independently selected from the group consisting of —H,—C(NHR)═N—OH, —NH—C(O)R, —NH—C(O)—NRR, —C(S)NHR, —C(O)NHR, —CO₂H, —NR₂,—C(NHR)═NR, —NH—(CO)—OR, —NH—SO₂—R, —C≡N, —OR, —SR, —SO₂R, —S(O)R, —NO₂,and trihalomethyl; where each R is independently selected from the groupconsisting of H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl and (C₂-C₈) alkynyl. 8.The compound of claim 5 wherein: a is an integer from 2 to 4; b is aninteger from 0 to 4; and c is zero.
 9. The compound of claim 8 wherein:a is an integer from 2 to 3; b is an integer from 0 to 2; R³ and R⁴ areeach independently selected from the group consisting of —H, halogen,—OR, and trihalomethyl; R⁵ is selected from the group consisting of —Hand —OR; R⁶ is selected from the group consisting of —H, —C(O)OR,—C(NH₂)═NOH and —SO₂R; R⁷ is selected from the group consisting of —Hand —C(NH₂)═NOH; R⁸ is selected from the group consisting of —H, —OR,—NO₂, —C(O)OR, —SO₂R and —C(NH₂)═NOH; and each R is independentlyselected from the group consisting of H, (C₁-C₃) alkyl, (C₂-C₃) alkenyl,and (C₂-C₃) alkynyl.
 10. The compound of claim 5 selected from the groupconsisting of FG 121, FG 122, FG 123, FG 124, FG 125, FG 126, FG 128, FG134, FG 202, FG 204, FG 206, FG 208, FG 1268, FG 1300, FG 1301, FG 1405,FG 1455, FG 1456, FG 1459, FG 1460, FG 1465, FG 1468 and FG
 1474. 11.The compound of claim 1 having the structural formula:

or pharmaceutically acceptable salts thereof, wherein a, b, c, Ar², andY² are as defined in claim 1 with the proviso that when a and b are 1and Ar² is phenyl, then c is other than
 0. 12. The compound of claim 11wherein Y² is selected from the group consisting of -halogen,-trihalomethyl, —R, —C(O)OR, —CN, —C(O)—NR—OR, —C(NRR)═N—OR, —C(O)—R,—C(O)NRR, —C(S)NRR, —C(NHR)═NR, —NRR, —NO₂, —NH—C(O)R, —NH—C(O)—NRR,—NH—C(O)—OR, —NH—SO₂—R, —NH—C(S)—NRR, ,—NH—C(O)R, —NR—C(O)—NRR,—NR—C(S)—NRR, —OR, —P(O)(OH)(NRR), —P(O)(OH)₂, —SO₂R, —S(O)—R, —SO₃H,—SR, and -tetrazole; where each R is independently selected from thegroup consisting of H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl, (C₂-C₈) alkynyl,(C₅-C₂₀) aryl, (C₆-C₂₆) alkaryl, 5-20 membered heteroaryl and 6-26membered alk-heteroaryl.
 13. The compound of claim 1 wherein Ar² isselected from the group consisting of phenyl, phenyl mono-substitutedwith Y², thienyl, and thienyl mono-substituted with Y².
 14. The compoundof claim 11 wherein Ar² is selected from the group consisting of phenyl,phenyl mono-substituted with Y² , thienyl, and thienyl mono-substitutedwith Y².
 15. The compound of claim 11 that is selected from the groupconsisting of FG 202, FG 204, FG 206, FG 208, FG 1455, FG 1456, FG 1459,FG 1460, FG 1465, FG 1468, FG 1471, and FG
 1489. 16. The compound ofclaim 1 wherein Ar² is phenyl substituted with one or more Y² with theproviso that when a and b are 1 then c is other than
 0. 17. The compoundof claim 16 wherein Y² are each independently selected from the groupconsisting of —R, —OR, —SR, —NRR, —NO₂, —CN, halogen, trihalomethyl,—C(O)R, —C(O)OR, —C(O)NRR, —C(NRR)═NOR, —NR—C(O)R, —NR—C(O)—NRR,—NR—C(O)—OR, tetrazol-5-yl, —NR—SO₂—R, and —SO₂R; where each R isindependently selected from the group consisting of H, (C₁-C₈) alkyl,(C₂-C₈) alkenyl, and (C₂-C₈) alkynyl.
 18. The compound of claim 16having the structural formula:

and pharmaceutically acceptable salts thereof, wherein R¹²⁵, R¹²⁶ andR¹²⁷ are each independently selected from the group consisting of —H,—OR, —C(O)R, —C(O)OR, —C(O)NRR, —C(NH₂)NOH, —NH—C(O)R, —NR—C(O)—NRR,—NR—C(O)—OR, —NR—SO₂—R, -tetrazol-5-yl and —SO₂R; and each R isindependently selected from the group consisting of hydrogen, (C₁-C₆)alkyl, (C₂-C₆) alkenyl and (C₂-C₆) alkynyl, with the proviso that when ais 1 then b is other than
 1. 19. The compound of claim 18 wherein Ar¹ isselected from the group consisting of phenyl, pyridinyl,1,3-benzodioxolyl, 1,4-benzodioxanyl, and thienyl.
 20. The compound ofclaim 18 that is selected from the group consisting of FG 1132, FG 1374,FG 1273, FG 1357, FG 1372, FG 1410, FG 1464, FG 1369, FG 1458, FG 1414,FG 1416, FG 1411, FG 1463, FG 1457, FG 1409, FG 121, FG 122, FG 123, FG124, FG 125, FG 126, FG 128, FG 134, FG 202, FG 204, FG 206, FG 208, FG1300, FG 1405, FG 1455, FG 1456, FG 1460, FG 1268, FG 1459, FG 1465 andFG
 1468. 21. The compound of claim 1 wherein each Y¹ is independentlyselected from the group consisting of —SO₂NH₂, —R′, —OR′, —SR′, —NR′R′,—NO₂, —CN, -halogen and trihalomethyl; each Y² is independently selectedfrom the group consisting of —R′, —OR′, —OR″, —SR′, —SR″, —NR′R′, —NO₂,—CN, -halogen, -trihalomethyl, trihalomethoxy, —C(O)R′, —C(O)OR′,—C(O)NR′R′, —C(O)NR′OR′, —C(NR′R′)═NOR′, —NR′—C(O)R′, —SO₂R′, —SO₂R″,—NR′—SO₂—R′, —NR′—C(O)—NR′R′, -tetrazol-5-yl, —NR′—C(O)—OR′,—C(NR′R′)═NR′, —S(O)—R′, —S(O)—R″, and —NR′—C(S)—NR′R′; each R′ isindependently selected from the group consisting of H, (C₁-C₈) alkyl,(C₂-C₈) alkenyl and (C₂-C₈) alkynyl; each R″ is independently selectedfrom the group consisting of (C₅-C₂₀) aryl and (C₅-C₂₀) arylindependently substituted with one or more —OR′, —SR′, —NR′R′, —NO₂,—CN, halogen or trihalomethyl groups.
 22. The compound of claim 1wherein Ar¹ is thienyl with the proviso that when a and b are each oneand Ar² is phenyl then c is other than zero.
 23. The compound of claim22 wherein each Y² is independently selected from the group consistingof —R′, —OR′, —OR″, —SR′, —SR″, —NR′R′, —NO₂, —CN, -halogen,-trihalomethyl, trihalomethoxy, —C(O)R′, —C(O)OR′, —C(O)NR′R′,—C(O)NR′OR′, —C(NR′R′)═NOR′, —NR′—C(O)R′, —SO₂R′, —SO₂R″, —NR′—SO₂—R′,—NR′—C(O)—NR′R′, tetrazol-5-yl, —NR′—C(O)—OR′, —C(NR′R′)═NR′, —S(O)—R′,—S(O)—R″, and —NR′—C(S)—NR′R′; each R′ is independently selected fromthe group consisting of —H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl and (C₂-C₈)alkynyl; and each R″ is independently selected from the group consistingof (C₅-C₂₀) aryl and (C₅-C₂₀) aryl independently substituted with one ormore —OR′, —SR′, —NR′R′, —NO₂, —CN, halogen or trihalomethyl groups. 24.The compound of claim 22 wherein Ar¹ is thien-2-yl.
 25. The compound ofclaim 24 that is selected from the group consisting of FG 1417, FG 1419,FG 1420, FG 1421, FG 1423, FG 1425 and FG
 1472. 26. The compound ofclaim 22 wherein: Ar² is selected from the group consisting of phenyl,phenyl independently mono- or di-substituted with Y², 5-10 memberedheteroaryl, and 5-10 membered heteroaryl independently mono- ordi-substituted with Y²; each Y² is independently selected from the groupconsisting of —R′, —OR′, —OR″, —SR′, —SR″, —NR′R′, —NO₂, —CN, -halogen,-trihalomethyl, trihalomethoxy, —C(O)R′, —C(O)OR′, —C(O)NR′R′,—C(O)NR′OR′, —C(NR′R′)═NOR′, —NR′—C(O)R′, —SO₂R′, —SO₂R″, —NR′—SO₂—R′,—NR′—C(O)—NR′R′, tetrazol-5-yl, —NR′—C(O)—OR′, —C(NR′R′)═NR′, —S(O)—R′,—S(O)—R″, and —NR′—C(S)—NR′R′; each R′ is independently selected fromthe group consisting of —H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl and (C₂-C₈)alkynyl; and each R″ is independently selected from the group consistingof phenyl and phenyl independently mono- or di-substituted with halogen,—NR′R′, —NO₂ or —CN, with the proviso that when a and b are each one andAr² is phenyl then c is other than zero.
 27. The compound of claim 22wherein Ar² is selected from the group consisting of thienyl,2,1,3-benzothiadiazolyl, imidazolyl, 1,7-thiazopyrrolizinyl, phenyl, andphenyl independently mono-, di- or tri-substituted with Y².
 28. Thecompound of claim 22 having the structural formula:

wherein R¹¹⁸, R¹¹⁹ and R¹²⁰ are each independently selected from thegroup consisting of —R′, —OR′, —OR″, —SR′, —SR″, —NR′R′, —NO₂, —CN,-halogen, -trihalomethyl, trihalomethoxy, —C(O)R′, —C(O)OR′, —C(O)NR′R′,—C(O)NR′OR′, —C(NR′R′)═NOR′, —NR′—C(O)R′, —SO₂R′, —SO₂R″, —NR′—SO₂—R′,—NR′—C(O)—NR′R′, tetrazol-5-yl, and —NR′—C(O)—OR′; each R′ isindependently selected from the group consisting of —H, (C₁-C₈) alkyl,(C₂-C₈) alkenyl and (C₂-C₈) alkynyl; and R″ is independently selectedfrom the group consisting of phenyl and phenyl independently mono-,di-substituted or tri-substituted with halogen or —CN, with the provisothat when a and b are each one then c is other than zero.
 29. Thecompound of claim 28 selected from the group consisting of FG 1302, FG1407, FG 1408, FG 1409, FG 1411, FG 1414, FG 1415, FG 1416, FG 1418, FG1422, FG 1424, FG 1457, FG 1461, FG 1463, FG 1466 and FG
 1469. 30. Thecompound of claim 28 wherein a is two, b is two and c is zero.
 31. Thecompound of claim 22 wherein Ar² is thienyl or thienyl independentlysubstituted with one or more Y².
 32. The compound of claim 31 having thestructural formula:

or pharmaceutically acceptable salts thereof, wherein: R¹²¹ is selectedfrom the group consisting of —R′, —OR′, —OR″, —SR′, —SR″, —NR′R′, —NO₂,—CN, -halogen, -trihalomethyl, trihalomethoxy, —C(O)R′, —C(O)OR′,—C(O)NR′R′, —C(O)NR′OR′, —C(NR′R′)═NOR′, —NR′—C(O)R′, —SO₂R′, —SO₂R″,—NR′—SO₂—R′, —NR′—C(O)—NR′R′, tetrazol-5-yl, and —NR′—C(O)—OR′; R′ isselected from the group consisting of —H, (C₁-C₈) alkyl, (C₂-C₈) alkenyland (C₂-C₈) alkynyl; and R″ is (C₅-C₁₀) aryl.
 33. The compound of claim32 selected from the group consisting of FG 1417, FG 1419, FG 1425, andFG
 1472. 34. The compound of claim 31 wherein a is two, b is two and cis zero.
 35. The compound of claim 1 having the structural formula:

or pharmaceutically acceptable salts thereof.
 36. The compound of claim35 wherein: Ar² is selected from the group consisting of phenyl, phenylindependently mono- or di-substituted with Y², 5-10 membered heteroaryland 5-10 membered heteroaryl mono- or di-substituted with Y².
 37. Thecompound of claim 35 wherein a is two, b is one and c is zero.
 38. Thecompound of claim 35 wherein Ar² is selected from the group consistingof thienyl, 2,1,3-benzothiadiazolyl, imidazolyl, and1,7-thiazopyrrolizinyl.
 39. The compound of claim 35 selected from thegroup consisting of FG 1367, FG 1361, FG 1362, FG 1363, FG 1365, FG1371, and FG
 1473. 40. The compound of claim 35 having the structuralformula:

or pharmaceutically acceptable salts thereof, wherein wherein R¹³⁰, R¹³¹and R¹³² are each independently selected from the group consisting of—R′, —OR′, —OR″, —SR′, —SR″, —NR′R′, —NO₂, —CN, -halogen,-trihalomethyl, trihalomethoxy, —C(O)R′, —C(O)OR′, —C(O)NR′R′,—C(O)NR′OR′, —C(NR′R′)═NOR′, —NR′—C(O)R′, —SO₂R′, —SO₂R″, —NR′—SO₂—R′,—NR′—C(O)—NR′R′, tetrazol-5-yl, and —NR′—C(O)—OR′; each R′ isindependently selected from the group consisting of —H, (C₁-C₈) alkyl,(C₂-C₈) alkenyl and (C₂-C₈) alkynyl; and R″ is selected from the groupconsisting of phenyl and phenyl independently mono-, di-substituted ortri-substituted with halogen or —CN, with the proviso that when a and bare each one then c is other than zero.
 41. The compound of claim 40selected from the group consisting of FG 1273, FG 1370, FG 1373, FG1369, FG 1357, FG 1360, FG 1410, FG 1372, FG 1368, FG 1364, FG 1366, FG1458, FG 1462, FG 1464, FG 1467, and FG
 1470. 42. The compound of claim1 wherein Ar¹ is benzodioxole and Ar² is thienyl or thienylindependently substituted with one or more Y².
 43. The compound of claim42 having the structural formula:

or pharmaceutically acceptable salts thereof wherein R¹²⁴ is selectedfrom the group consisting of —R′, —OR′, —OR″, —SR′, —SR″, —NR′R′, —NO₂,—CN, -halogen, -trihalomethyl, trihalomethoxy, —C(O)R′, —C(O)OR′,—C(O)NR′R′, —C(O)NR′OR′, —C(NR′R′)═NOR′, —NR′—C(O)R′, —SO₂R′, —SO₂R″,—NR′—SO₂,—R′, —NR′—C(O)—NR′R′, tetrazol-5-yl, and —NR′—C(O)—OR′; each R′is independently selected from the group consisting of —H, (C₁-C₈)alkyl, (C₂-C₈) alkenyl and (C₂-C₈) alkynyl; and each R″ is selected fromthe group consisting of phenyl and phenyl independently mono-,di-substituted or tri-substituted with halogen or —CN.
 44. The compoundof claim 43 wherein a is two, b is one and c is zero.
 45. The compoundof claim 43 selected from the group consisting of FG 1367, FG 1361, FG1371 and FG
 1473. 46. A compound having an inhibitory effect onC-proteinase, said compound having the formula:

or pharmaceutically acceptable salts thereof, wherein: g is an integerfrom 1 to 4; h is an integer from 0 to 4; i is an integer from 0 to 4; Zis selected from the group consisting of (C₃-C₁₀) cycloalkyl, (C₃-C₁₀)cycloalkyl independently substituted with one or more Y⁵, 3-10 memberedheterocycloalkyl, and 3-10 membered heterocycloalkyl independentlysubstituted with one or more Y⁵; Ar⁶ is selected from the groupconsisting of (C₅-C₂₀) aryl, (C₅-C₂₀) aryl independently substitutedwith one or more Y⁶, 5-20 membered heteroaryl, and 5-20 memberedheteroaryl independently substituted with one or more Y⁶; each Y⁵ isindependently selected from the group consisting of a lipophilicfunctional group, (C₅-C₂₀) aryl, (C₆-C₂₆) alkaryl, 5-20 memberedheteroaryl and 6-26 membered alk-heteroaryl; each Y⁶ is independentlyselected from the group consisting of —R′, —OR′, —OR″, —SR′, —SR″,—NR′R′, —NO₂, —CN, -halogen, -trihalomethyl, trihalomethoxy, —C(O)R′,—C(O)OR′, —C(O)NR′R′, —C(O)NR′OR′, —C(NR′R′)═NOR′, —NR′—C(O)R′, —SO₂R′,—SO₂R″, —NR′—SO₂—R′, —NR′—C(O)—NR′R′, tetrazol-5-yl, —NR′—C(O)—OR′,—C(NR′R′)═NR′, —S(O)—R′, —S(O)—R″, and —NR′—C(S)—NR′R′; each R′ isindependently selected from the group consisting of —H, (C₁-C₈) alkyl,(C₂-C₈) alkenyl and (C₂-C₈,) alkynyl; and each R″ is independentlyselected from the group consisting of (C₅-C₂₀) aryl and (C₅-C₂₀) arylindependently substituted with one or more —OR′, —SR′, —NR′R′, —NO₂,—CN, halogen or trihalomethyl groups, with the proviso that when g and hare 1, i is 0, and Ar⁶ is phenyl, then Z is other than C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-lower alkyl, N-lower alkyl-piperazino-lower alkyl,(morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl orN-lower alkylpiperidyl)-lower alkyl.
 47. The compound of claim 46wherein g is two and i is zero.
 48. The compound of claim 46 wherein: Zis selected from the group consisting of adamantyl, cyclohexyl,morpholino, tetrahydrofuranyl, piperidyl, and piperidyl mono-substitutedwith Y⁵; Ar⁶ is selected from the group consisting of phenyl and phenylmono-substituted with Y⁶; and Y⁵ is —(CH₂)_(n)-phenyl, where n is aninteger from 0 to
 3. 49. The compound of claim 46 wherein Ar⁶ is (C₁-C₆)alkoxyphenyl.
 50. The compound of claim 49 having the structuralformula:

or pharmaceutically acceptable salts thereof.
 51. The compound of claim50 selected from the group consisting of FG 1131, FG 1306, FG 1335, FG1379 and FG
 1380. 52. A compound having an inhibitory effect onC-proteinase, said compound having the structural formula:

or pharmaceutically acceptable salts thereof, wherein r is an integerfrom 1 to 4; s is an integer from 0 to 4; Ar¹¹ is selected from thegroup consisting of (C₅-C₂₀) aryl, (C₅-C₂₀) aryl independentlysubstituted with one or more Y¹¹ 5-20 membered heteroaryl, and 5-20membered heteroaryl independently substituted with one or more Y¹¹; G isselected from the group consisting of:

R⁹⁰ and R⁹¹ are independently selected from the group consisting ofhydrogen, (C₁-C₈) alkyl, (C₂-C₈) alkenyl, (C₂-C₈) alkynyl, (C₃-C₁₀)cycloalkyl, (C₅-C₂₀) aryl, (C₅-C₂₀) substituted aryl, (C₆-C₂₆) alkaryl,(C₆-C₂₆) substituted alkaryl, 5-20 membered heteroaryl, 5-20 memberedsubstituted heteroaryl, 6-26 membered alk-heteroaryl, and 6-26 memberedsubstituted alk-heteroaryl; R⁹² is independently selected from the groupconsisting of hydrogen, (C₁-C₈) alkyl, (C₂-C₈) alkenyl, and (C₂-C₈)alkynyl; and each Y¹¹, R⁹³, R⁹⁴, R⁹⁵, R⁹⁶, R⁹⁷, R⁹⁸, R⁹⁹, R¹⁰⁰, R¹⁰¹,and R¹⁰² is independently selected from the group consisting of anelectron-donating functional group, an electron-withdrawing functionalgroup, and a lipophilic functional group.
 53. The compound of claim 52wherein Ar¹¹ is selected from the group consisting of (C₅-C₂₀) aryl and(C₅-C₂₀) aryl independently substituted with one or more Y¹¹.
 54. Thecompound of claim 53 wherein each Y¹¹ is independently selected from thegroup consisting of -halogen, —R, —OR, —SR, —NRR, —NO, —NO₂, —CN,-trihalomethyl, and —SO₂NH₂, where each R is independently selected fromthe group consisting of —H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl and (C₂-C₈)alkynyl.
 55. The compound of claim 52 having the structural formula:

or pharmaceutically acceptable salts thereof, wherein: R¹⁰³, R¹⁰⁴, R¹⁰⁵,R¹⁰⁶, R¹⁰⁷ are each independently selected from the group consisting ofhydrogen, halogen, —R, —OR, —SR, —NRR, —NO, —NO₂, —CN, -trihalomethyl,—C(O)R, —C(O)OR, —C(O)NRR, —C(O)NRR, —C(NRR)═NOR, —C(O)NROR, —SO₂NRR,and —NRSO₂R; where each R is independently selected from the groupconsisting of H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl, and (C₂-C₈) alkynyl.56. The compound of claim 52 which is selected from the group consistingof:


57. The compound of claim 55 having the structural formula wherein r is2, s is 2, and R¹⁰⁶ and R¹⁰⁷ are each hydrogen.
 58. The compound ofclaim 52 wherein G has the structural formula:

and pharmaceutically acceptable salts, wherein: R93, R⁹⁴, R⁹⁵, R⁹⁶, R⁹⁷and Y¹¹ are each independently selected from the group consisting of-halogen, —R, —OR, —SR, —NRR, —NO, —NO₂, —CN, -trihalomethyl, and—SO₂NH₂; where each R is independently selected from the groupconsisting of H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl, and (C₂-C₈) alkynyl.59. The compound of claim 58 having the structural formula:

wherein: R¹¹¹ and R¹¹² are hydrogen; R¹⁰⁸, R¹⁰⁹ and R¹¹⁰ are eachindependently selected from the group consisting of —H, —R, —OR, —SR,—NRR, —NO₂, —CN, halogen, trihalomethyl, —C(O)R, —C(O)OR, —C(O)NRR,—C(NRR)═NOR, —C(O)NROR, —SO₂NRR, and —NRSO₂R; and each R isindependently selected from the group consisting of H, (C₁-C₈) alkyl,(C₂-C₈) alkenyl and (C₂-C₈) alkynyl.
 60. The compound of claim 59wherein r and s are
 2. 61. The compound of claim 60 having thestructural formula:

or pharmaceutically acceptable salts thereof.
 62. The compound of claim52 wherein G has the structural formula:

and R⁹⁸, R⁹⁹, R¹⁰⁰, R¹⁰¹, R¹⁰² and Y¹¹ are each independently selectedfrom the group consisting of -halogen, —R, —OR, —SR, —NRR, —NO, —NO₂,—CN, -trihalomethyl, and —SO₂NH₂; where each R is independently selectedfrom the group consisting of —H, (C₁-C₈) alkyl, (C₂-C₈) alkenyl, and(C₂-C₈) alkynyl.
 63. The compound of claim 62 wherein Ar¹¹ is phenylindependently substituted with one or more Y¹¹.
 64. The compound ofclaim 63 wherein r and s are two, having the structural formula:

R¹¹⁶ and R¹¹⁷ are each hydrogen; R¹¹³, R¹¹⁴, R¹¹⁵ are each independentlyselected from the group consisting of —H, —R, —OR, —SR, —NRR, —NO₂, —CN,halogen, trihalomethyl, —C(O)R, —C(O)OR, —C(O)NRR, —C(NRR)═NOR,—C(O)NROR, —SO₂NRR, and —NRSO₂R; and each R is independently selectedfrom the group consisting of (C₁-C₈) alkyl, (C₂-C₈) alkenyl and (C₂-C₈)alkynyl.
 65. The compound of claim 64 having the structural formula:

or pharmaceutically acceptable salts thereof.
 66. A pharmaceuticalcomposition comprising the compound of claim 1, 46 or 52, and apharmaceutically acceptable carrier, diluent or excipient.
 67. A methodof treating a disease related to inappropriate or unregulated productionof collagen, said method comprising the step of administering to asubject in need thereof an effective amount of a compound according toclaim 1, 46 or
 52. 68. The method of treating a fibrotic disorderselected from the group consisting of hepatic cirrhosis and arthritis,said method comprising the step of administering to a subject in needthereof an effective amount of a compound according to claim 1, 46 or52.
 69. A zinc ion coordinating reagent, said reagent selected from thecompounds of claim 1, 46, or
 52. 70. The method of inhibiting an MMP,said method comprising the step of administering to a subject aneffective amount of a compound according to claim 1, 46, or 52.